Lecture 17. Terpenes and Cell Signaling, Part 1.

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Lecture 17. Terpenes and Cell Signaling, Part 1.
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Lec 17. Introduction to Chemical Biology -- Terpenes and Cell Signaling -- Part 1
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UCI Chem 128 Introduction to Chemical Biology (Winter 2013) Instructor: Gregory Weiss, Ph.D. Description: Introduction to the basic principles of chemical biology: structures and reactivity; chemical mechanisms of enzyme catalysis; chemistry of signaling, biosynthesis, and metabolic pathways. Index of Topics: 0:06:34 Terpene 0:08:55 Biogenic Head-To-Tail Synthesis of Terpenes 0:14:41 Protein Prenylation: Localizes Protein to the Membrane 0:18:03 Bisphosphonate: Anti-Osteoporosis Drugs 0:20:27 The Rich Structural Diversity of Terpenes 0:34:51 Cyclization of Isoprene Oligomers 0:39:51 Control Over the Central Dogma 0:42:22 Ancient Small Molecules with Bioactivity 0:46:08 Arrows in Chemistry and Biology 0:49:11 Cell Signaling Scenarios 0:54:50 The 7 Signaling Pathways 0:56:16 Genetics to Dissect Complex Biology 1:01:06 Small Molecules Offer Control Over Otherwise Unavailable Phenotypes 1:07:48 Nuclear Hormone Receptors 1:18:14 In Vivo Biosynthesis of Calcitriol 1:19:23 Restoring Biological Function of a Mutant Vitamin D Receptor
Flüchtigkeit Activation energy Activity (UML) Cell fusion Wursthülle Chemistry Reactivity (chemistry) Diterpene VSEPR theory Enzyme Cell (biology) Colourant Tandem-Reaktion Ballistic trauma Controller (control theory) Chemical structure Posttranslational modification Active site Cell biology Periodate Terpenoide Cyclische Verbindungen Pyrophosphate Setzen <Verfahrenstechnik> Naturstoff Area Perfumer Grading (tumors) Rock (geology) BET theory Pyrogallol Topicity Addition reaction Multiprotein complex Chemical reaction Chemistry Erdrutsch Anomalie <Medizin> Electronic cigarette Azo coupling Triterpene Chemical compound Cell (biology) Terpene Pharmacy Thermoforming Hydrocarbon Sequestrant
Enzyme inhibitor Chemical bond Phosphorus Resonance (chemistry) Prenylation Growth medium Electrical breakdown Death Memory-Effekt Set (abstract data type) Chemistry River source Cancer Diterpene Molecule Klinisches Experiment Wine tasting descriptors Enzyme Protein subunit Electric arc furnace Natural rubber Thermisches Kracken Bisphosphonate Phenylalanine Ballistic trauma Protein Phosphate Stratotyp Posttranslational modification Öl Synthetic rubber Cell membrane Biochemistry Enzyme inhibitor Surface science Reaction mechanism Walking Chemist Topicity River source Chemical reaction Multiprotein complex Apatite Food additive Wine tasting descriptors Osteoklast Camphor Phosphate Protein Azo coupling Chemische Synthese Powdered milk Bisphosphonate Chemical compound Cell (biology) Biomolecular structure Stuffing Ionenbindung Recreational drug use Activity (UML) Plasma protein binding Peptide Density Pyroclastic rock Chemical plant Organische Verbindungen Wursthülle Soil conservation Island Cell (biology) Isoliergas Tandem-Reaktion Active site Butcher Process (computing) Polypropylene Pyrophosphate Setzen <Verfahrenstechnik> Area Metal Potenz <Homöopathie> Substrat <Chemie> Recreational drug use Pyrogallol Carbon (fiber) Cell membrane Natural rubber Ice Diterpene Metabolic pathway Functional group Grease (lubricant) Chemical structure Base (chemistry) Pharmacy
Lebensmittelfarbstoff Astaxanthin Florence Gene Cholesterol Chemistry Block (periodic table) Diterpene Wine tasting descriptors Tiermodell Enzyme Fire Electron Proton-pump inhibitor Colourant Elimination reaction Oxide Periodate Cyclische Verbindungen Hydride Periodic acid-Schiff stain Octane rating Concentrate Nobelpreis für Chemie Walking Tuberculosis Pigment Florence Chemical reaction River source Stockfish Electronic cigarette Wine tasting descriptors Paste (rheology) Reducing agent Medicalization Phosphate Tiermodell Azo coupling Chemical compound Zellmigration Medical history Thermoforming Butter (2011 film) Biomolecular structure Hydrocarbon Stop codon Steroid Sense District Ionenbindung Biosynthesis Complication (medicine) Nutrient Wursthülle Aromaticity Columbia Records Methylgruppe Sample (material) Diet food Island Ageing Chemische Synthese Tandem-Reaktion Cryogenics Orange juice Precursor (chemistry) Ausgangsgestein Elektronentransfer Acetyl-CoA Setzen <Verfahrenstechnik> Area Metal Biosynthesis Precursor (chemistry) Singulettzustand Malerfarbe Carbon (fiber) Ice front Spawn (biology) Hydrogen Gesundheitsstörung Diterpene Retinoid Separator (milk) Farmer Pharmacy
Dye Ionenbindung Doppelbindung Peroxide Wetting Florence Honey Hydrogen peroxide Wursthülle Chemical reaction Solution Aromaticity Chemical reaction Hydrogen Diterpene Hydrogen Tiermodell Colourant Blind experiment Cobaltoxide DNA replication Periodate Process (computing)
Chemistry Medicinal chemistry Pharmacist Molecule Diterpene Glutamic acid Enzyme Tidal race Protein Elimination reaction Organic food Cell membrane Hydrophobic effect Cyclische Verbindungen Lysergic acid diethylamide Octane rating Concentrate Walking Deep sea Topicity Isopren Cancer Chemical reaction River source Death Nuclear receptor Systemic therapy Stream gauge Tyrosin Multiprotein complex Copolymer Enzyme Microtubule Azo coupling Molecule Chemical compound Cobaltoxide Medical history Hexamere Stuffing Acetylcholine Activity (UML) Peptide Hyoscyamin Chemical plant RNA Wursthülle Nuclear receptor Columbia Records DNS-Synthese Ring strain Agonist Cell (biology) Transcription (genetics) Controller (control theory) Active site Tool steel Sea level Side chain Taxol Process (computing) Area Setzen <Verfahrenstechnik> Naturstoff Potenz <Homöopathie> Precursor (chemistry) Asset Malerfarbe Carbon (fiber) Man page Synthetic oil Metabolic pathway Agonist Coordination number Chemical structure Base (chemistry) Mixing (process engineering) Carboxylierung Pharmacy
Starvation response Activity (UML) Insulin Pheromone Atomic orbital Glucosetransportproteine Wursthülle Organische Verbindungen Nuclear receptor Chemistry Atomic orbital Sample (material) Molecule Cell (biology) Transcription (genetics) Protein Data conversion Insulin Transformation <Genetik> Organic food Sea level Butcher Periodate Mucin Setzen <Verfahrenstechnik> Area Homocysteine Trauma (medicine) DNS-Synthese Singulettzustand Chemist Hybridisierung <Chemie> Coal Chemical reaction Chemistry Wine tasting descriptors Zeitverschiebung Lone pair Branntwein Azo coupling Molecule Chemical compound Cell (biology) Wound Crack cocaine
Homocysteine Setzen <Verfahrenstechnik> Embryo Lysergic acid diethylamide Meat Death Structural analog Solution River source Molecule Wine tasting descriptors Tyrosin Rapid Orlistat Protein Colourant Organic food Ion channel Toxicity Enzyme inhibitor Cell growth Octane rating Walking Pigment Minimale Hemmkonzentration Chemist Multiprotein complex Memory-Effekt Wine tasting descriptors Death Nuclear receptor Glutamic acid Systemic therapy Stream gauge Tyrosin Multiprotein complex Enzyme Azo coupling Tidal race Molecule Chemical compound Cell (biology) Adhesion Inhibitor Thermoforming Sense District Fibroblast growth factor Acetylcholine Stimulant Ocean current Wursthülle Nuclear receptor Diet food Agonist Meat analogue Island Cell (biology) Transcription (genetics) Epidermal growth factor Pigment Controller (control theory) Mortality rate Soil Mutagen Magma Precursor (chemistry) Hope, Arkansas Tool steel Kernproteine Signal transduction Cell biology Adhesion Sea level Butcher Pain Fatty acid synthase Mucin Setzen <Verfahrenstechnik> Area Death by burning Heterodimere Precursor (chemistry) Polycyclische Aromaten Genotype Induktor Vietnamese people Ingredient Sea level Metabolic pathway Agonist Signal transduction Transforming Growth Factor beta Generic drug Chemical structure Recreation Pharmacy
Sense District Wursthülle Molecule Sample (material) Chromosome Meat analogue Cell division Hardness Cell (biology) Lactitol Protein Library (computing) Tool steel Inhibitor Organic food Process (computing) Setzen <Verfahrenstechnik> Metabolite Fluorescence Walking Assembly (demo party) Chemist Chromosomenaberration Food additive Genotype Wine tasting descriptors Metabolic pathway Microtubule Molecule Chemical compound Pharmacy Stuffing
Lysergic acid diethylamide Cell growth Metabolism Protein domain Binding energy Metabolic pathway Gene Cytoplasma Alpha particle Klinisches Experiment Molecule Enzyme Fire Transkriptionsfaktor Protein Elektrolytische Dissoziation Chemical structure Cell membrane Metabolite Lysergic acid diethylamide Cell growth Elektrolytische Dissoziation Cellular differentiation Gas Binding energy Gene Nuclear receptor Tiermodell Cast iron Transcription (genetics) Azo coupling Gonadotropin-releasing hormone Chemical compound Cell (biology) Common land Stuffing Biomolecular structure Condensation Starvation response Sense District Testosterone Heterodimere Radiation damage Estran Differential calculus Ligand Nuclear receptor Wursthülle DNS-Synthese Hydroxybuttersäure <gamma-> Cell (biology) Transcription (genetics) Östrogenrezeptor Controller (control theory) Gene expression Open reading frame Kernproteine Sea level Ligand Process (computing) Aldehyde Area Compliance (medicine) Heterodimere DNS-Synthese Estran Metabolic pathway Grease (lubricant) Chemical structure Mortality rate Pharmacy
Phytosterol Combined oral contraceptive pill Binding energy Hydro Tasmania Cholesterol Klinisches Experiment Dibutylphosphat Tyrosin Cortisol Enzyme Fire Electron Basal metabolic rate Pharmaceutical drug Chemical compound Derivative (chemistry) Regulatorgen Concentrate Binding energy River source Chemical reaction Nuclear receptor Tyrosin Iodide Inflammation Chemical compound Chewing gum Steroid Sodium chloride Complication (medicine) Mill (grinding) Pentose phosphate pathway Nuclear receptor Wursthülle Diet food Cell (biology) Mortality rate Arginine Vitamin Sea level Ligand Aldehyde Setzen <Verfahrenstechnik> Calcitriol Tumor Neprilysin Biosynthesis Metabolism Precursor (chemistry) Iodine Genotype PH indicator Salt Derivative (chemistry) Steroid Pharmacy Sodium iodide
Setzen <Verfahrenstechnik> Cell (biology)
OK we're back will slow this morning and we're going to finish up terpenes today and they want to sell signaling which is Chapter 9 the last chapter in the book and this is 1 of my all-time favorite chilies and that's saying a lot because some of the volatility and heads up I want to thank you with the mystery here which side you look closely as the color of the hair of these women versus this guy over here that even a little bit of a mystery explain more very shortly and
OK take a quick look at Chapter dying to skim through it and has a ton of really useful information especially the go on in biology or anything related Beghal attracted 19 is too orient you in this enormous and daunting C biological literature when you open up Science Nature sell it seems like every new paper tries to redefine cell signaling and adds an additional layer of complexity and the truth is as a chemist this is the exact opposite of the way we like to think chemistry we like to have a few very simple rules that we can use to understand all of cell biology all of our sorry all of can all of chemical reactivity biology seems to be going inadvertent direction but it that it needed to be that complicated and so the bullet Chapter 9 is to simplify all that daunting complexity stripped it down to a few essential elements that if you learn that you can understand anything that you encounter in area cell signaling and I'll be exploiting every shortly today OK proposals the coming out there doing days 48 hours again attacked a self-addressed stamped on beloved you want comments back if you don't want comments back that's quite all right on it but it's essential that you follow instructions upward to turn in about comments before and if you're done at this point wondering how you could possibly improve I try to write more concisely so concession is an essential element of good writing the more concisely the more precisely right that fewer number of words the better I told you can use up to 10 pages but if you use fired and your very effective arguing so much the better OK you'll be more effective as a US proposal writer and someone being hit out persuasive if he can use fewer words your words is always better than more work OK any questions about the proposal this is your last shot last answer questions OK let's start with you suggest so the tournament outcome would say so I'm not OK :colon really is this Thursday yes I assure you it's Thursday I will take it a lot but I honestly amenable Thursday it's OK but thanks for the the headset and then a question back worse no no no no and thank you for asking a Pentagon Lily different format than the Journal article reported actually at the bottom of the instructions posted to the website I tell you exactly what kind of Thornton margins of looking for so I'm looking for axes double spaced 12 . 1 inch margins but I think it's all specified on the server Towards the End of instructions a don't follow the Journal article for that's a different assignment for this assignment I'm looking for proposal has different sections etc. But of cell securing busy ahead of the other questions Our it's good luck I cannot wait to read your original creative ideas but this is really 1 of the most 1 things for me to do is actually read about these clever schemes and I'll probably have a back you within a week so that when I returned frequently writes on 0 1 last announcements had altogether slide about this 1 by Chanel said please fill please read the class evaluate the Class 3 Tripoli this is especially important if there's a chance that I might be writing a letter of recommendation for you when I write letters of recommendation I always type in the ID number has let's get completely led by type and ID number and that you know addresses and do this idea complete record of all the grades and something else that pops up is whether or not the student actually provided feedback and that's randomized that the feedback is stripped from 90 but I just give me a list of all the names of everyone who provided I information and so on but if I can also criteria 2nd lists of people who didn't provide feedback and my feeling is that ,comma spent an hour or so working on your behalf to help you go to dental school or whatever you could spend 10 minutes working on my behalf Celtic possible therefore next-generation OK so if you want a letter of recommendation for me be shortage the lot of those evaluation forms and any other questions about any announcements things like that were going right right down to the last 2 matches we have so much to talk about so what we have operated on OK so sorry so more announcements undeniable have office hours tomorrow this is your final all bets are off time to ask me anything about the proposal I imagine that we not asking me a really crucial questions I'm hoping that at this point your ideas are pretty well that we will have discussions sections this week and the discussion sections will again have the format office hours seeking coming 100 questions answered critic has been sick for for the last couple days a public should be back today it will soon present a I'm a rock stars active today that she tells me that she's going to be there Miriam has office hours yeah could you move this to make it actually useful that would be great without thinks makes the I'm OK .period like that that's less than half of it's so we saw last time is that the Turpin class of hydrocarbons that are there are naturally synthesized and they are astonishing in their diversity and the biological activity I should mention to you that these are the compounds that make perfumes smell good that make up flavors taste good use of the compounds of life that make life worth living in a way of these are the things that we sense and we enjoy sensing so these are all assembled from Isa Supremes and had detailed fashion and I'm actually going to start this today's lecture by taking this topic up again and looking a little greater detail and on we talked about how these linear isup annoyed Pyro all states such as spotted seal bypass a juror during prostate etc. can be cycle eyes terpenes and basis and the terpenes today's folded up and then hits it with this cycle Asian reaction which was the cargo Kanye cascade that leads to these complex natural products today we're gonna look at the actual ,comma had hands as they go flying through the air as they go on to make really complex natural products and this is I think 1 of those objects of wonder that I truly amazed me about the debt for world I and then we also discussed very briefly that Europeans are often oxidized after the site was a should step so after sequestration there is a series of tailoring enzymes that then took the skeleton of a hydrocarbon and Modified Modified Modified until a and you ended up with this very bioactive compounds such as tax all of which is used routinely in anti-cancer therapies and to repeat since cases as we discussed offer remarkable control over Riccio and stereo specificity and that's how you can have 1 enzyme that gives you a particular Rene fusion say a 660 Asian versus a 75 or even aspire refuse where the 2 rings wrapped right angles to each other and this is truly amazing chemistry and it requires a catalyst that has been that has evolved to have real control the catalyst really exerts control over this Riccio and serious specificity OK and I
want to start with this idea of head to tail diffusion I kind of presented this without really describing in great detail and and I wanna go back over it just very briefly that this is a familiar molecule to us line many in this is derived from 2 I Supreme subunits and on if we call this sort of this top part with the team at the graves the head of the user fit together in the head to tail fashion over here and there and I guess it's kind of tales submittal fashion on the side but I'm even before the chemistry that I'm showing you was defined or other organic chemists have recognized that terpenes always seem to follow this head to tail role and I this is actually a pretty powerful way of figuring out how these things are chemically synthesized our supersize not chemically in a laboratory but synthesized by microorganisms and plants that have these terpenes based pathways so the way this work is and then there's the joining that we talked about last time between the heads and tails and then we have a X media group over here this is our Pyro phosphate that leaves and that sets you up for a site was a shot to give you this line compound and will appear in greater detail but short this is going to set the 0 chemistry it's intercepted this common double liners .period attack over here etc. what's OK so very briefly head tail emerges from and how these things are synthesized this tale over here at the pirate prostate Didier made ppb damnable Alkire a prostate as this could be great good reading group steps out the door setting us up with this ,comma cannot and then the head Of the IPP Lisle Pitino pyroclastic can attack that gives you naturally this is the the tale over here head over here so I had detailed joining and that happens every time OK there's no lose 1 really for inmates an exception to that but for the most part these things are held together and attached together and had detailed fashion and so and this gives us a really important rule for dissecting how these things have built yeah yeah I read yes yet but it's in residence with this a little like position to give you a tertiary cover powder but only the primaries reacted the tertiary over here is held distant from this nucleophilic old bid over here said because it held the way it's not available for the reaction only the primary covered Haddad and rabbits residents so in the resonance structure you're going tertiary Primary Tertiary Primary Tertiary Prince but the primary gets the reaction and then the machetes principal driver contemplation of 5 2nd a sweet that in 1 direction and I'll be honest of these of this class of compounds that seems to ignore many of the rules that you learned about in the camp 81 and software organic chemistry where we learned about stability of our current patterns that have dominated the stability of the tertiary cover pattern is versus secondary or primary and I'm in this class of compounds and this classes in places we find that the enzymes themselves are capable of overcoming those bias seats and they overcome it by stabilizing preferentially 1 ,comma pattern which another and I'll show you all are all briefly surprised too to imagine that actor speculate that site would have something Hungary right above this primary covered had to give it a little extra stability for example you could imagine an aromatic functionality appear of phenylalanine a trip that the that would be precisely poised to do they are can iron pies stacking event and therefore stabilize the primary cover had preferentially over the much more beguiling tertiary ,comma pattern that otherwise would be the dominant more stable ,comma had and I thank you for asking as 1 of the really intriguing aspects of this class of compounds and it blows me away every time OK
so when we look at the structures that I showed you last time notice that all joined together and had detailed fashion so we have tale head tail had steelhead steelhead steelhead tail had deal until had and this can go on for a really long time like an and being a thousand the case natural rubber but they're all joint head to tail had detailed 1 after another and the all too weak in that fashion without nose scrambling because the enzyme that warms these bonds is only set out to do ahead to kill joined hands on In synthetic rubber chemist try to emulate that kind of had detailed fashion type of joining as well and said I'm in synthetic rubber and rubber this had detailed joining years is set into place by I'm starting with some sort of pen-based nucleophile so this is Olivia alleviate their this is basically a Caribbean island Caribbean 9 attacks the tale of ice agreed that sets you up of new nuclear that new Caribbean island on this new head carbon and that sets you up to attack another tale etc so this actually works really really well on with I want to pick up our discussion and show you a different aspect of Turkey chemistry and the different aspects of the the neatly leads us toward cell signaling which is the final topic of this class it turns out that the localization of proteins in the cell it is vitally important to dictating their functions in other words you can have this really really active enzyme that I can turn on all kinds of things in the cell but if it's not available that somehow square squirreled away somewhere in the cell then it would have the effect on cell signaling so getting the protein to the correct place is a really important challenge in on it biochemistry in chemical and ourselves biology and there's a couple of different ways that proteins that are suited to the cracks spot in the cell 1 way for example a short peptide tags that active zip codes to direct proteins to specific areas within the cell another way this force proteins to be had with I supra derived by Supreme derived tales of cases such as these sealed tells added onto their own protein grass Dewar whereas the Jedi GTP the peso here's the protein over here it has a violated hazardous esteem by all recall the file sets you up to have violate pH 7 quite readily on this file amended tax authorities sealed power across state has catalyzed by Bonesteel transferees and this will give you a Bonesteel attached to the file OK so now you have this greasy part over here where you think this thing school localized to variable little bit of priests would proceed tale and membrane indeed break the memory is a big greasy space as well so this acts as a greasy spike that drives this that drives right into the membrane and anchors the protein permanently on the plasma membrane and that has important consequences of skipping over some other steps some other modifications that take place as well but this basically takes last and confines it to a two-dimensional surface on the upper half of the part of our 2 metal surface on the barrier of the cell and that kind of confinement is really important for its activity so because Rossi plays a key role in the conservation cell signaling that there that attempts to To do realist process and inhibit seal transferees so this party still transferees important targets for 80 concerts therapeutics and unfortunately none of those have worked out in the clinic what ends up happening is they're so non-specific for roster of getting our foreign isolated versus other proteins getting furnace later that they have not been very effective in the clinic unfortunately because otherwise look like a really promising approach OK so if we can disrupt this type of localization then we have a way of dealing with cell signaling in many different kinds of cells and here's another example of this is this is an example of a problem the cell signaling of austere class so austere blossomed austere classic 2 types of cells that control the buildup and breakdown of the bone tissue so the bones the stuff that your bones are made out of and undersea becomes especially important as as people age their bones tend to get more brittle and so it becomes really important to inhibit austere class Witcher which are breaking down the bones and so 1 way of approaching that is to to inhibit spotted seal their prostates states so if you inhibit this enzyme here there on you be preventing this foreign insulation this foreigners still bypassing from foreign insulating the proteins is going and then killing the Aussie of plaster of Paris so the goal here is to inhibit this process here and the strategy is to provide these kind of drugs that musical bisphosphonates and these look I guess if you kind of look really sleep identity is becoming a look like the substrate right and you really have to sweat but you could definitely see that inherent to this Boston 8 right where there's a carbon phosphorus bombs hence the name boss made these bisphosphonates because they have to have these on sort of looked like the bypass states of the pirate prostates of Geraghty of 5 and then some of these even has some greasy tales as well they these compounds are prescribed in large quantities to women especially as they get older but also meant as well depending on the circumstances and In order to In order to direct them directly to the of those there often times there they point very strongly to hydroxy apatite which is 1 of the 5 he crossed a key constituents for building bones .period bone and bone density the peso and the Singapore osteoporosis treatment questions it's so I want a return to where we left off last time in terms of complexity and on last time I showed you how the terpenes and bases worked but we did get a chance to really zoom in and look at the about 10 cascades and so on this seems like an appropriate point to pick things up so here is an example of different terpenes found you know nature of these include the monitor opinions which are Odyssey 10 so all of these consists of 2 I Supreme units joined and head to tail fashion but the CES which Europeans which 50 again all of these have 3 i Supremes and then the dike terpenes see twenties that have by Supreme subunits and on again if we were and we spend time looking at this will find that all of these are an odd to all these I joined and head to tail fashion sometimes it gets complicated fine but it's the definitely in there OK so how do you get this rich structural diversity and you control this compound versus this compound treatment yes something like camphor reverses this carrying over here and the answer is by controlling the mechanistic pathways
of this cycle is a should processes that synthesize the compounds and so the terpenes places that I described on Thursday or exceptional really at directing the outcome of a really complicated series of reactions and so the 1 I want to start when it is In implicated in the biosynthesis of vested I'll so In this case the enzyme outsiders Quilliam nostril Cyclades takes this a pox on and itself OK when it does that the next step in here is a cargo can and our was Asian reaction where each 1 of these electrons hot pot so it starts here hops here tops there and in the end you end up forming 1 2 3 for carbon-carbon bonds in 1 neat step on showing it to you as a concerted reactions meeting all 4 bonds are performed in a smooth pathway and and this is 1 of the areas where chemists have been arguing for years about whether all this takes place a one-step or not and to my mind the definitive experiment was done by the ETA Corey who showed pretty pretty conclusively that actually the sort of multiple intermediates their form during these comic highlights stepped up and said I'm showing you all all 5 hopping along the once it probably doesn't happen exactly like that so after this Scarborough kind cycle after this acquisition cascade this compound here produced you're all current account and undergoes a series of methyl transfer events where high drives and metals all the ones highlighted in pink over here hop around and moving migrate and on by doing this this gets you to eventually led Oster all of which then becomes the basis for I'm so this this becomes the basis that all humans 0 it's a case this the cover carrots accusations that all of you are doing even as we speak kind of many just getting you started with where these hydride ships are going so after the cascade you end up with the tertiary carbon had rate here the others tertiary care would had the 1st hydride ship is the 1 to hydride ship where this hydride in a in this age that Spain hops over the here giving you a new new tertiary covered had so let's think about this revival how might the enzyme preferentially stabilized 1 cover can intermediate over another and try this reaction on I'll the view that I really talked about today Chelsea indeed arrival than Chelsea so you can imagine over here there might be an aromatic ring that's available to do a account Hi stacking to preferentially stabilized this problem had had over the other tertiary ,comma pattern appear on all these things are directed he can have you know sort of random jumping around the ring of all this is carefully controlled by the enzyme and and absence of enzyme what's more likely to happen is that the elimination and none of these hydride migrations but these hydride migrations a really profound right over here and there used to be and methyl group over here it's now hopped over years the methyl group that was over here is hopped over to hear the hydrogen over here overhears hopped over hear the hydrogen that was here hopped over there so it's it's like a whole series of 1 2 metal and high drive shafts where everything in the seems to be on fire in some way and capable of migrating and movement over and I have it's like a game of musical chairs where the final stop the final cover Caroline is simply the most preferentially stabilized likely as Chelsea pointed out through the headline PPI and stacking type interactions makes sense parent of humans and unfortunately cannot synthesize retina and this is a really important and I really think nutrition issue in developing countries so the regulates awaits result from an unusual tailored to tail joining of that OK so here's journey Algeria I prostate and a 2nd jury Algeria like phosphates and check this out there going through an unusual Taylor Taylor joining events appear that almost never happens it happens in the super long journal Algeria phosphate cases but for for the most part this is rare right and every other supreme in joining head tail fashion and now here's to tales that coming together as catalyzed by note he said that it's OK there's a couple more enzymes that go through here and then you get down to the familiar beta-carotene of parents right that's nice orange color that we create so much about the colors essential it's not just that it's colored orange and makes you know it that I was gonna make joke but it would be inappropriate and like it is useful because it plays important roles in our human biology and so on but for example if you have a diet that's missing this beta-carotene you end up with all kinds of unusual diseases that are really seen in developed countries like the UK but evidently important in developing countries and so 1 of the challenges is trying to come up with diets that that that meet the nutritional requirements of a separate sample of urine and waste dependent diet and 1 way to do this would be to insert the genes that synthesized beta-carotene into rice resulting in Nice orange-colored rights it's called golden rice and using that as a way providing nutritional requirements for for the people in those countries this is really important this is really something I think all of us should be on the front lines working on this is the kind of thing that makes a really big difference in the world OK so alas less weighty issue but 1 that really surprised me when I 1st encountered it and this is a more trivial applications and it turns out that farmed salmon is farmed in a way to I'm sure that you can actually dial and the color of the salmon results and the end on farmers fish farmers on do this by being the salmon these precursors to this passes the emptying of pigment a Casey could basically with the salmon fits this some of the on over here you can dial in exactly the color salmon that is going to be most appealing to the market and if you can't Albertson's you shake your head but history go Albertsons and that salmon is of particular shade of pale that's going to best appeal to Europe the Irvine consumer OK and it's all totally controlled by simply being in the right precursor chemicals so that an the the fish had this past as the unpaid this is necessary because of wild salmon will be wants assurance that naturally make their own asses and the shrimp and there and be the salmon that are formed in big hands don't encounter shrimp as much and so on on and that would be very different color you wouldn't want to keep the of non-peak salmon K would be appealing so anyway principle as the beta-carotene similar chemistry as well but and then again you to Stalin's using different unit Island the final color based upon different concentrations of these precursors OK so I went to
6 years now I've been talking to you but mainly about the human examples of butter beans and I would talk to you just very briefly about the nonhuman examples of this is that this is so my all-time favorite paintings anywhere these were done in the 15th century by the grace of Sandro Botticelli and the truly sublime appendices 15th century and of these look astonishingly modern even today I mean they just exquisite portraits in this case is the use of the birth of units and on this cases is that of the Primavera that I showed on the very 1st like that OK so even the best scientists like to take vacations and the great ,comma block winner of the Nobel Prize in chemistry for In a lot of the chemistry of showing each day dealing of hydrocarbons working out things like HMG CoA reductive is working out a lot of the synthesis of cholesterol that I should be showing over the last 2 lectures that was all worked out by the great ,comma block OK so he's on vacation in Florence Italy and he's looking at these paintings in real life but for the 1st time and on the extraordinary thing noticed was that all of the models in these paintings and all the things I have 1 here to women in the this is a kind of a surprise to us it is if you're in Italy on most of the women have brunette hair they have dark brown hair and other thing that struck him was that these were painted in the 15th century Whereas hide oxide which is the the most common method for and colorizing here from converting from oxidizing here pigments from brunette to blonde was not invented until 1880 said understood this is heightened outside was invented by the Nazis in 1818 so presumably they these are the women did not have access to large quantities of stocks so an obvious question to a biochemist lie ,comma block is how these women end up with blond hair pay or maybe the artists completely fabricated the whole 1 hair of hands and if you look at lots of other paintings from the same time period it's very clear that 1 here was something of a craze and pay so and comments on vacation and he likes mysteries owned by the way he wrote it's sublime book called up once in Venetian paintings armadillos and other medical mysteries highly recommended great book but anyway so he's on vacation he starts looking to this further and when he finds is that the
women on in that period would understand a large amount of time combing terpenes into their here's a case so they would they would have this kind of Wet Willie's solution that they would come into their here and then they would have to leave that kind of wet here hanging out in the sun for long periods of time and what happens is a very inefficient chemical reaction that results in production of attaining a little bit of hydrogen peroxide and over time this will gradually lightened the hair color OK so here's this works starting without the help of pleading and chlorophyll you know from the point of this is derived from floor appeals the triplets sensitize their that allows you to do basically deals all the reaction would be the oxygen and then here's the light over here so this converts the singlet oxygen to the triplet state of oxygen the trip would sensitize the giving you an oxygen oxygen double-blind recall that oxygen is almost all oxygen were breathing is oxygen oxygen single bond anyway so this gives you an oxygen double bonds which sets you up for for this steals all the reaction giving you a proxy intermediate back and then decompose to form a super-duper stable aromatic compounds and releasing hydrogen peroxide high during practice I can indict the hair kind of 1 color you know this is not exactly you know blond 1
but it's you know certainly honey blonde right on and you know the process might take a really long time but the results you know were fashionable that questions about this they wanted to this experiment for me I had to like to see this replicated I'm reading about 4 years never seen a replica I understand it takes hours but the funds are rights and let's talk
about others acquisition reactions by the chooses things they're really complicated uh if you are get into this and in greater detail on here for example is that tax tiny precursor to tax all and the on public health and site was that this goes through it is on pretty challenging prey were gonna do and we're going to do a nucleophilic attack on a primary coverage and we've seen that before we saw that on an earlier flight will be joined together the head detail but I Supreme precursors of there's then another site position to give us a tertiary ,comma power and then beat elimination over here so this state elimination gives us this to Selene intermediate protests as an intermediate can then be coordinated in a couple of different places and In his kind of an astonishing steps OK so what we're going to see is a coordination of all of that and just take a moment to take a deep breath and appreciate that majestic unbelievable mess carries about it all opinions are not great basis right there is really no way that this step over here should take place but it does the enzyme has evolved under very effective acid backing Prodi nature of this this this all up and giving us a new tertiary ,comma kind and and setting us up for the last cycle is Asian which then leads to a lot of elimination to give us the tax dying skeletal and that becomes the core performing Taxol and this is really astonishing chemistry this is pretty remarkable stuff I am OK then after you get attacked a dying over here you get to tax all area anyone speculate on identity of this acid over here and what kind of assets would you find site so someone Chelsea yes what's that Spartacus suggested that would be my 1st race as well as Spartacus said 1 glutamic acid the problem with those know is they have oxygen nucleophile right both of those carboxyl accountants have oxygen it's an oxygen is a really great nuclear and the problem there is that you have all these ,comma kinds of flying all over the place and time oxygen and carbon don't mix the oxygen is liable to go winging its way ,comma kind giving you a permanent covalent intermediate so instead when we look closely at the structures of terpenes and bases that do this type of chemistry we find a completely different acid inactive site it's not which or Spartacus so and there was an excellent choice it was my 1st choice as well as it turns out is not the case other choices whatever kind of assets would you find inapposite of enzyme cannot begin with a His history yeah yeah so history and that's a good choice as well yeah I can argue that 1 hour that's a good run and I'll tell you that that would defend the tyrosine is actually the choice so tyrosine which has hasn't been all side-chain actually acts as the acid to do this predation step and that's completely counterintuitive because the PKK of the Noland tyrosine might be 10 or something like that and here it is acting as an acid the protein 8 something new he doesn't wanna get credited so you can imagine that neighboring side chains must in some way turbocharged the acidity of the tyrosine making this reaction possible this is pretty extraordinary chemistry a rate of any questions about our terpenes polypeptides that class of molecules pass molecules we've been saying character questions about once a Venetian paintings Chelsea focus attacks all that is a really effective until that kills off the neighboring microbes so Microsoft's emphasize this as a way of killing off the neighbors to compete but we chemists and other medicinal chemists and pharmacists and physicians price tax all these very effective at inhibiting microtubule of plumbers station and deep organization and the fact is that it's very effective in the anti-cancer therapies so it prevents cells from cells-about dividing and ends up killing of breast cancer cells for for example the rights of other any other thoughts yeah it's moving on
but I want to switch gears now were now in Chapter 9 of the final chapter final topic for the book and I am in a way ,comma saved the best for last we really had to learn everything that we've learned this quarter so that we can understand and systems level how cells really work OK so we can now put together all of the information I forgive you all course and now think about cells in a really chemical way upon specifically we've been talking about the Central Dogma biology and were now ready to talk about how natural products and to do that and synthetic molecules again and disrupt the process used in on different steps of the Central Dogma and again because natural products sci-fi enzymes these enzymes down here sizing things and I we're going to be most interested in those that are interfering with the transcription small molecules in general offer some really powerful abilities to control prophecies in the cell for 1 thing but you have control over when they're applied OK so what this means then is you can have on an organism that's grown to a certain stage of development and then you give it the chemical compounds and you shut down a pathway that specifically at certain stages development and that allows you power you unless you really powerful tool to ask it's so at this stage in development and how those of have protein pathway had a pathway actually impact on development of the organisms for that matter you also have on spatial control so I told you about was temporal patrol spatial patrol meaning that you can doze in a specific type of a specific site in order in the organism for example you might be interested in understanding either no just kidding OK or it was just say just liver and how signaling by liver cells affects other organs so you can imagine was small molecules giveaway that and just dozing Ingersoll ever and not the other on pathways in order in organisms so this temporal and spatial control is really powerful it's 1 of the great strains abusing synthetic molecules as tools to dissect these pathways and so on that's Oregon be talking about for the next couple of days as we discussed small-molecule control over the Central Dogma this is then done for thousands of years OK there's evidence suggests that goes back to you writings on Egyptian papyrus you can actually find descriptions of small molecules that are isolated from the on plants like this 1 so for example from this plant this this we're looking at plant over here you can actually isolate highest Committee which is isolated again from the plant depicted over here this is known as belladonna nightshade had been Mandrake and it has the structure of of the structure appear notice that its structure mimics the structure of a single calling upon this is when you don't really have to squint at East you look really similar to each other especially when you draw like this a here's the structure of support will be another related compound in that and so these compounds act as agonists versatile Coleen receptors and on these compounds are found in really high concentrations in eyes seeds and berries of these plants because on it encourages animals to grab onto the seeds and berries and move them around dusk on spreading the plant to make more successful as a Darwinian evolved creature OK so we humans are are also very big on on a psychedelic experiences and so we also priced the seeds and berries and I will tell you that you should carefully read the warnings if you start experimenting with these these are really come down very very serious side effects and even death and but for centuries of these have been used and they work again by targeting a seal culling receptors which I believe we talked about in the context of paralysis right so for example which is a who you know for centuries were thought to fly there probably flying metaphorically using compounds like these isolated from other belladonna nightshade another other plants and in a straightforward way that they would do this if they take the seeds and put a man on various membrane passengers rights of nose etc. and actually it works they they worked surprisingly there is a high concentration of these compounds in the state case was
in addition to humans as wanting to spread these things as small molecules are used by other animals to signal each other so for example the avocado mon shown here on response to the spirit of this compound over here and this is active powerful way that we can use to track the past 2 attractive but this is a fair amount that it uses to attract mates OK so long as signaling by small molecules is used for therapeutics it used to be a book by organisms to signal each other it's used and recreationally it's used in all kinds of different contexts and on it's pretty much universal every organism that we find even the most simple organisms even something like the coal wide use small molecules to talk to each other so this really is a universal mode of communication and on this kind of astonishing that we humans actually used different modes for communication were not so dependent upon us but your dog the dog is very dependent on sales on small molecule signaling as evidenced by the fact that it spends all its time sniffing right you don't a rich universe of small molecules all around it when it's sample census in the year OK but
before get into how the small molecules work we have to have a little chat about heroes and this aside from experience I know that this is 1 of the big hang-ups that organic chemists have when they start diving into cell signaling errors in chemistry and errors in biology at 2 fundamentally different meetings in the chemistry worlds and we have areas that indicate transformations from reactants going to products often with some catalysts and these errors can be equilibrium errors they can be a single .period arrows indicate no return reaction but this is a familiar to us that there for that matter were also very familiar with areas that show electrons and for overlap the orbitals from the highest occupied orbital the Homo of this nucleophile lone pair to the lowest occupied molecular orbital of the electrify all over here they said these are areas that we use conversation late all the time in this class and other classes and I've been using these from that since the very beginnings classic use them today multiple times and totally understood heroes in biology means something different for the 1st time when there is an error in the area of means that directly at the direct activation OK so for example 1 of the best era indicated his lagging and points to its receptor over here which in turn lines too this time foreign isolated protein over here and furthermore if this isolated protein does some transformation it's going to be acting as a catalyst and the way the indicate its catalyst is the way we indicates the calluses chemical transformation by simply placing it in the center of Aero OK now there's a whole bunch of other areas that we find in on biological communication so for example an error that has to be Terminator at and I don't even know what you call us anyone want crack that would you call this and . 1 area the perpendicular line that indicates that direct intervention OK so this would be so somehow this guy over here directly inhibits this protein over here so it's a guideline it indicates indirect innovation meeting leaders an intermediary said this guy buys this guy would fight as that which somehow inhibits this a case of gas lines indicate indirect effects and Saul lines indicate that and then finally the era that has the aura monitor that indicates activates transcription of so all of these areas is a kind a language of biology they follow these conventions the really not that I don't think if we take a moment to think about it Eric within cell signaling there's trees in areas of the world on the euro's services we don't talk about that anymore OK we're going to be using them that's where that's the conventional wrote to follow up with insults said delay there's going to be 3 kinds of us city areas for cell signal and of each of these scenarios of all depending on the requirements of that type of cell for example on the left you can imagine single arrives and then the cell has to immediately respond in that case the cell will release something that its preset the size and no transcription is required so the signal never reaches down to the level of transcription of DNA an example of this I'll show you on the next flight it's the release of music by goblet cells from another type of signal in signal rise the cell then has to synthesize a proteins and respond to that signal transcription is required if transcription is required things slow down the OK so this is a slow type of signal over here for example on skin cells that have to deal in a wound Casey put your finger on it with some papers something like that of the skin cells nearby have to proliferate and in that injury and so on this this is not going to happen instantaneously right you know that it takes a couple of days for a on the paper cut to heal right it doesn't happen instantaneously didn't have to happen instantaneously for that matter and so this is a slow type of cell signaling uncommonly this a slow and a fast response for example in response to insulate so insulin arrives the cell immediately starts are responding using the glucose transporters that we discussed when we talked about the like of biology of a few weeks ago on but in addition to the sale has to respond to this insolence by and synthesizing new proteins and having a slow response so this hybrid is I'm also a very common mode as well his surrogacy these 3 different scenarios play out on the
1st scenario is that this is about nuisance so for example a single Coleen agonists it buys a stake mean stimulates intestinal global Boblett goblet cells to spell out said in a rapid response from Kaiser this is you you're eating up something you can something that's better like this Pfizer and you have to really respond to that you know your stomach doesn't like their stuff and so the stomach and intestines respond by secreting all this news and we talked about the structure amusing it's analogous sack arrived and that helps smooth the passageway and get rid of this bitter tasting compound OK so here's the Boblett goblet cells over here they've already stored up all the music OK it's already over here so as soon as this is your calling agonists arise you immediately start spewing out of the news and it flows out into the intestines and it's already you know I'm increases the size so that no DNA transcription is required to get an immediate response OK now on a Mossad trying to systematized cell going so also on the level of system at to systemized system at a station cells can either be talking to each other to different kinds of cells or they can be talking to the same class itself and on these 2 different classes of cell signaling are referred to as the the crying appear crime or a crime is communication between cells of the same type places if there is a goblet cells are stimulated each other and that would be our prime it however the dependent on different classes cells to stimulate them that would be characterized that makes sense OK now it turns out that within all of biology there's really only 7 different types of cell signaling OK and I want to make this point lose super-duper reported because when you pick up the literature in cell biology and signaling it's insanely confusing and complex cut through all the complexity all that matters is that there are 7 different types of cells signal if you learn the 7 different types of cell going you understand all of the different kinds of pathways that are written about in the current literature case and 1 of the the problems with the focus on get off the track I can't resist a case so out of 1 of the things that makes this difficult is on when biologists right about their own pathways there was described the pathways unique and how does this nonsense that every single pathway can be fit into 1 of the 7 categories every year and as a chemist and I want to know the 7 simplest examples and I want to be able to apply the 7 simple examples to every other example it's out there and I promise you that you can do this this will make sense of all of cell signaling OK so all we have to do over the next couple days is if we learn about these different types of receptors in my Ganz and their cell signaling track transduction pathways that modulate transcription and this is going to simplify it and otherwise ridiculous level of complexity this gives started
this is so this diagram is really basically all you have to know the shows the 7 different types of cell signaling starting with the most common nuclear receptors said nuclear receptors are controlled by like hands that reach directly into the nucleus and turn on transcription hence the name nuclear receptors pain and I'll show you examples of each of these are also at the top are two-component pathways where you have on a dimerization event up here that eventually reaches down to 2 transcription and note again that the stash lines indicate indirect effects so this case the wagons can go all the way into the nucleus in this case there so it's going to have a whole bunch of intermediaries they're going to have multiple steps to eventually get to the nucleus and in addition we have receptor tyrosine kindnesses trying Myrick death receptors g protein coupled receptors financial receptors and finally gas receptors and on from there found all of cell signaling that can fit into the 7 categories so it is learned the 7 and then I hope everything else will make sense the summer complained let's get started on the start of the most common which nuclear receptors and will set the will stepped on systematically through each of these so I'm OK before I get to that I have to introduce a couple more terms on the 1st of these odd terms that are taken directly from the area of genetics and the and the terms are lower genetics versus reverse genetics and on the best example I can give you this Aja suffer loss so fruit flies naturally have red eyes and on the you radiate a whole population of fruit flies for you you feed themselves or a chemical mutagens you will eventually find fruit flies that have white guys OK they will have this white phenotype OK they look like this red-eye wide-eyed I am and then if you spend time looking at the different mutations that result in the white but you will figure out that actually this results from cared that mutations that prevent the previous pigment precursors that result in the red-eye from getting across the Solomon rates OK so wide eyes result from mutations that prevent this pigment precursors that eventually result in the red eyes over here OK so this approach is called forward genetics you make a whole series of random mutations and then you look at the types of phenotypes that result from those random mutations and use those different random mutations to dissect the biology and that results in those phenotypes pact that's called there were genetics to make mutations you look for a response you don't understand how that response occurred in the office said it would be the reverse genetics not exactly opposite but it's complementary on before I get to reverse any questions about our genetics play said lower generics random mutations hopes for an interest in tired of this is strategy has worked well for over 100 years but I'll just doing for a really long time chemists had in the last couple of decades applying each day on actually know I'd say this is going on for much longer time than say in these 5 decades maybe even longer ,comma submitted applying a chemical analogs of there were genetics called the word chemical genetics where you apply a bunch of different small molecules to induce rain changes and you hope to find it interesting being type became so maybe have your fruit flies you apply a bunch of agrochemicals of fruit flies and you look for ones that give you I'm white allies chemicals that result in wide eyes and then that identifies chemicals that are in some way preventing the patients from reaching the highest give you the red color of the fruit flies came here is 1 example of this this is a compound called rapper Meissen isolated from Easter Island soil from the straw islands offered up and out in the Pacific this compound in the very center acts as the glue In a molecular wedged between the epic 506 binding protein 12 has much-awaited 12 helicopters and another compound called mammalian target rapper recognizance and to work OK so this is a KDP unelected purple and tour on the right ingredients and you could see that the rapper license is acting as the meat in the sandwich to bring together this complex and the net result is that once this complex forms the but the rapper Meissen prevents amongst other things I T cells from forming and so rapid is a really important and you know suppressor I think we talked about this before actually maybe a couple of times this class this is a molecule that prevents the Union system from a responding to a liver transplants of high has so again and this is called lowered chemical genetics because really random compounds that are isolated from some soil from like a distant islands and then we're going to look for ones that have interesting facts in this case that the 2 types of suppressing the immune system and that we use the compound to study how it how these immune system pathways were so recognizes that a really powerful compound bigger for dissecting these pathways and only in recent years has also had reported that important tool it's been an important region instead it's in studying in Beijing and of diet and other types and other types of pathways OK so small molecules control offer control other over otherwise unavailable phenotypes and so for this reason they're really beaten by they've come to the floor as really good power tools in and in cell biology so for example but that the classical genetics approach starts to break down when you get mutations that killed on the organism OK so for example this focal adhesion trainees but if you make mutations that focal adhesion Friday's you end up with these you know on the embryos their hugely distorted and really capable of living space is indeed the classic genetic Bowa genetics of approach not going to work so instead which you do is you identify a small molecule inhibitors of vocal adhesion ,comma highways and offers a solution and that inhibits focal adhesion coyotes and gives you a way of studying this otherwise lethal phenotypes so that we can dissect how the protein actually works right now
costs of doing this requires out some way to look for interesting phenotypes right we need some way to to go out and identified in poor chemical genetics and hear the other cellular phenomenon and so on chemists have been very clever about doing this but this is key experiment done by turning Purpura and I Mitchelson and on what they did is they had a whole library at different compounds here's 1 compound shown here and they start with 16 thousand compounds and in a way that it has a large number of wells they look for some might find a signature pay which has this dark blue collar this they set up an assay that looks for a particular phenotype dark will under that asset of and then they take the compounds that light up in this assay and look for the fact that look for the compounds that can stabilize microtubule formation as earlier we talked about tax all but here's a tax stabilizes microtubules here's another contest compounds 52 of these destabilize microtubule formation 1 stabilizers that and the compounds that are positive here then go on to fluorescence like crossing the experiments over here these are low throughput over here these are high throughput over here yet 16 thousand compounds down here you have less than 100 staring at cells under a microscope that's hard work pay over here they're just looking for the 1 . spot out of you know thousands tens of thousand of exports that's easy this step over here can be done by robots this step over here can be done by robots as well but sometimes the robots this stuff sometimes the imaging software misses really interesting effects OK and what was to poor and colleagues found out is that this compound called Monastir all has this really astonishing effect on on the kinetic or which is this assembly on the chromosomes during cell division the peso normally that the chromosomes up kind of like on the forgetting my football analogy scrimmage line of scrimmage sorry but they said everything lines up on this line of scrimmage during cell division and then these chromosomes are pulled apart into the 2 daughter cells explodes the whole thing and so instead of having chromosomes in the center microtubules homicides instead you end up with chromosomes on outside and this crazy microtubules in the center and that's absolutely fascinating it turns out that this compound is an inhibitor of 1 of the motor proteins that provides the chromosomes and pushes and shoves Acromas-owned into place during this process and selected you really powerful tool for dissecting how How cell division takes place
OK so many questions about using small molecules in this yet he said that this year on the use of my time here exactly time the problems went on exactly and all the units they didn't expect to have you know something like this but they weren't looking for this pattern they were just looking for weird patterns in the same way that you look for wide eyes or just weird colored or creatures in the case of the fruit flies with a sample the discipline looking for something that's abnormal and then he went you find that abnormal thing you go ahead and use this as a tool to figure out how this process works and what proteins must be implicated so this implicated in a motor protein called Neeson as particular type of indecent in this process that otherwise it wasn't clear exactly what I was doing some very powerful tools appear question about the yes yes I was a bit dominant respect that the dominant mutations the new predominance together and then you deftly said if it's recessive then you don't see it 1 out of every 4 young daughters 1 of 34 progeny that's the genetics the Agnellis also it's complicated because of depends on how many occasions a required it starts to get complicated quickly but my genetics friends could tell you all about the it but it makes sense right that yes you see those mutations coming through whereas if you use a small molecule you know what's a small molecule is of metabolites once high realised-a whatever oxidized it's game over its effects disappear and that too is powerful right to apply a small molecule and then it goes away and you can go back to wild-type and say could see what it looks like a small molecules not there in exactly the same organism OK right so I want to get back to the 7 different kinds now we understand that how small molecules are going to play important roles and going to highlight the importance of the walls of the small molecules as he start looking at the 7 different pathways for cell
signaling and 1 of the most common of these cell signaling pathways are the nuclear hormone or that the nuclear receptor I have based pathways there is some 28 nuclear receptors only 8 I have well well identified I've known like and as recently as a couple of years ago OK so these are depicted here so some of these are familiar to us I believe we talked about that I and the cited these widening I needed hormones earlier in the quarter but we talked earlier today about the process of supersizing as estrogen which eventually could be further modified to give us extra dial here's testosterone area years Khalsa trial over here and these are all steering receptors right all these guys here theorize that these guys down here already know a cast iron fiery these other on hormones these hormones .period directly to nuclear receptors and an association moment nuclear receptors directly carry the signals all the way to the DNA level and note that when these things are bound in these hormones every year abound here completely and goal by the proteins and the protein throws a big old floppy hug around this year right over here and it's completely buried OK so in this space filling model you don't see any yellow pad it's completely covered up the thing is on heavily varied widely but what the by the receptor the receptor changes confirmation upon binding to the hormones and that in turn allows us to do stuff like that get into the nucleus and start affecting transcription
note by the way I told you that a better known as the 20 sort of unknown it's thought that those other 20 and buying Tiberius metabolites weekly OK but meeting not very strongly and so that finding is thought to be a little nonspecific and a way of sampling many different states in the South the difference that steps along metabolism and other intermediate compounds as well OK so when we take a look at their 2 modes of nuclear receptor signaling that we need to learn about 1 of these fears and illustrated by estrogen so here's estrogen over here and in the hypothalamus in the hyperbolic neurons in this city in the estrogen vines to the estrogen receptor estrogen receptor then associates from the heat shock protein and that frees up estrogen receptor to eventually make its way to the declares in what you need to know about this is that estrogen receptor binds to the estrogens the steroids and that it gets all the way to the nucleus it doesn't get to the nucleus before then because this kind of covered up by these heat shock proteins and furthermore it has the blind to this 1 Carrick firing data European bot Bader molecule adhere to make it through the nuclear poor and be imported into the nucleus once it's there a condensed trigger transcription of the good troop in receptor triggers the transcription and that in turn then and allows the cells to respond to the estrogen some important something else that's a notable about this notice that this has the a homodimer it is a 2 identical molecules of estrogen receptor alpha over here and then estrogen receptor over here and they're both identical contrast that against the other the nuclear receptor signaling which involves heterodimers agent saying principle the molecule fuses in this case the molecules ran out of gas said structure is here opened by the way again this structure arrested as you dialed again synthesized from 1 nostril Radanova Casanova here can directly speak its way across the plasma membrane through the cytoplasm through the nuclear membrane and get all the way over exists on this receptor for the better gasses in the acid receptor alpha and on to this also binds to the there are X are receptor and then the 2 these get-together in heterodimers rise before leading to and the production of these Houllier domain encoded proteins OK so this leads to transcription and expression eventually these talks the protein effects on both cases we see a similar effect you have this greasy little hormone molecule the greasy hormone molecule gets into through the plasma membrane binds to the receptor and then the receptor sneaks into the nucleus where it can cause transcription OK so in this case the signaling molecule is on taking a shortcut to get all the way to the nucleus surrounded they can let's look at a structure and so on this is a structure of the Peapod damage should this you should be gamma binding to red receptor alpha on Ballard also 2 this light and over here Rossi Glenn with his own I and ready note gasses in and yellow up here and then also binding to DNA so this is an example again of Harare dimerization do purple people are down arts are out and and then this heterodimers can interrogate the DNA I'm using exactly the same sort of on the a transcription factor event that we talked about what we talked about proteins bind to DNA many weeks ago effect may be over a month ago it seems like a really long time earlier in the quarter and and again notice that this has LB Kiel 2nd snugly fit into the major and interrogate sequence so this they will then look for a particular sequence of DNA and then activate transcription of a particular 1 gene particular open reading frame of that DNA leading to the turning on of a specific program proteins the production of specific proteins make sense OK so much talk about here In fortunately I just don't have time to running out of time suffice it to say chemists have spent a lot of time thinking about ways to control nuclear receptors because if you can then you can dramatically control gene transcription in turn that could have dramatic consequences for controlling the growth of cells the mortality of cells and the differentiation of sales etc. In and but
this is where this has been done classically after well over 50 years now for example isolated from the Bob Bosco yelled this company the check out this to this thing is enormous right that that the whole to wear down here this is what the entry looks like it's just 1 monster tuba you can isolate from this this tumor this compound dials Jenin and Brandise Jenin and you can make a strong you can make a whole bunch of others this year steroids and aren't you could imagine wanting to make this for birth control pills for hydrocortisone for entire inflammation predators other information affects etc. OK on nowadays are so Back in the fifties and sixties a whole series of chemists a whole generation a chemist went to Mexico that where the Bob Bosco Yemen has been cultivated for centuries they went to Mexico in an isolated directly out of these very high percentages of their precursors like this 1 for synthesizing these formats and nowadays we found that even though the present at lower concentrations in soybeans because soybeans or so are grown so and at the grown so ubiquitously and at such high levels in the United States that we can regulate we can we can much more simply isolate Fido steroids durals directly from soil and so the ultimate source nowadays of many of our past your rights is on from fighters durals itself rather than the pro-Moscow again which is too bad because the yen has a wonderful cultural heritage of other
nonsteroidal against nuclear receptors include these Widodo countdowns to try the Pyrenees and touches of detector I try over firing over here on the important thing to know about this is that both of these compounds are derived from tyrosine this is alienated tyrosine and these are important for regulating the basal metabolic rate and so if your diet does not have enough iodine in it and you could run into all kinds of complications occur including going to that shown here and I put that picture out because I suspect known as classrooms has seen a case of queer eye is to be totally comment until all assaults in the country except for kosher salt was iodized so what this means is that there is a low concentration of sodium iodide mixed in with the sodium chloride and it turns out that doesn't require a very high concentrations of iodine iodide died in the diet to get just enough to synthesize naturally these I higher than needed but tyrosine derivatives are its presence in dealing with the nuclear receptors OK it 1 last thought that comes to trial but this compound over here on requires that you be light for an Electra cyclic during opening reaction so you start of the hydro cholesterol that compound does is very weird 6 electron Elektra cyclic reopening electrons are getting bounce bounce bounce and honesty during the opening and then there's a 1 7 Sigma Tropic ship shown by these errors every year which you might have to go home and convince yourself of yourself on but long story short this gives you vitamin D 3 and if you have up at other deficiency in vitamin D this leads to rickets the bow-legged phenomenon this is just 1 of 1 of the many nasty manifestations of this really terrible disease on but again but the key is that in our diets we get enough vitamin D 3 and this leads to liver enzymes Acadians signs that converted to Kelso trial and they Khalsa trial binds directly to nuclear receptors OK final thought last flight of the day but if for example you have a mutation in the Council trial receptor indication of this the arginine over here Tennessee you can chemically synthesized I'm talking like you do this in laboratory then you give it a pharmacist accusative position you could have a chemically synthesized derivative of Khalsa trial that then fills in the mutation over here wines the receptor and gives you a normal cell signaling that while 1 we stop here
we come back this time will be looking at the other 6 types of cells


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