Lecture 16. Glycobiology & Polyketides, Part 2.

Video in TIB AV-Portal: Lecture 16. Glycobiology & Polyketides, Part 2.

Formal Metadata

Lecture 16. Glycobiology & Polyketides, Part 2.
Alternative Title
Lec 16. Introduction to Chemical Biology -- Glycobiology & Polyketides -- Part 2
Title of Series
Part Number
Number of Parts
CC Attribution - ShareAlike 3.0 Unported:
You are free to use, adapt and copy, distribute and transmit the work or content in adapted or unchanged form for any legal and non-commercial purpose as long as the work is attributed to the author in the manner specified by the author or licensor and the work or content is shared also in adapted form only under the conditions of this license.
Release Date

Content Metadata

Subject Area
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: 0:00:33 Polysaccharides 0:08:45 Fatty Acid Synthase: Paradigm for a Polyketide Synthesis Machine 0:10:58 Plasma Membrane = Lipid Barrier 0:13:44 Hydrolysis of LIpids in Cell Signaling 0:15:26 Prostaglandin Signaling to Coordinate Cell Response 0:16:15 Leukotrienes Mediate Inflammatory Response 0:19:09 Shutting Down the Prostaglandin Pathway at its Start 0:23:39 Converting Fats into Soaps 0:25:54 Diversifying Products from Polyketide Synthases 0:39:54 Fatty Acid Synthase (FAS) Has a Circular Assembly Line 0:44:18 Terpenes: Built from Isoprene (5C) Units 0:56:18 Inhibition of Cholesterol Synthesis 0:57:48 Cyclization of Straight-Chain Precursors by Enzymes
Semiotics Carbohydrate Surface science Polysaccharide Süßstoff Molecule Triterpene Klinisches Experiment Orlistat Protein Data conversion Chewing gum Surface science Omega-6-Fettsäuren Concentrate Gelatin Topicity Cancer Multiprotein complex Chemical reaction Wine tasting descriptors Electronic cigarette Alpha-1-Rezeptor Branch (computer science) Chemische Biologie Connective tissue Acid Soft drink Sucralose Protein Azo coupling Chemical compound Medical history Butter (2011 film) Biosynthesis Ionenbindung Reaction mechanism Sunscreen Wursthülle Food Diet food Inflammation Cell (biology) Sea level Glycosylation Conformational isomerism Glucose Composite material Biosynthesis Oligosaccharide DNS-Synthese Polysaccharide Gezeitenküste Gesundheitsstörung Functional group Breed standard Chemical structure Separator (milk) Base (chemistry) Satellite DNA
Hydride Reaction mechanism Reaction mechanism Gas Asset Protein domain Alcohol Chemical reaction River source Paste (rheology) Condensation Enzyme Fire Protease Cell (biology) Hydrolysat Osmosis Active site Condensation reaction Medical history Carboxylierung NADPH Catalytic converter
Starvation response Recreational drug use Activity (UML) Density Set (abstract data type) Cytoplasma Wursthülle Molecule Deterrence (legal) Enzyme Solvent Plastic Cell (biology) Lactitol Protein Lipide Organic food Solubility Extracellular Cell membrane Area Surface science Vimentin Composite material Omega-6-Fettsäuren Amine Chemist Phospholipase Erdrutsch Cell membrane Water Hydrolysat Functional group Chemical compound Cell (biology) Acetone Pharmaceutics Lipide Chemical structure Base (chemistry) Wasserbeständigkeit Thermoforming Stuffing
Weakness Macrophage Asthma Stimulant Wursthülle Chemical reaction Molecule Enzyme Fire Cell (biology) Tandem-Reaktion Common land Library (computing) Active site Transformation <Genetik> Pain Conjugated system Hydrophobic effect Area Setzen <Verfahrenstechnik> Biosynthesis Omega-6-Fettsäuren White blood cell Leukotriene Wine tasting descriptors Volumetric flow rate Functional group Inflammation Molecule Chemical compound Cell (biology) Chemical structure Gene duplication
Soap Metabolic pathway Block (periodic table) Medicinal chemistry Molecule Ethanol Enzyme Rapid Lipide Protein Prostaglandine Chemical structure Posttranslational modification Spring (hydrology) Inhibitor Cell membrane Doppelbindung Omega-6-Fettsäuren Walking Bioavailability Chemical reaction Erdrutsch Electronic cigarette Hydroxide Wine tasting descriptors Symptom Systemic therapy Hydrolysat Acid Glycerin Arachidonic acid Inflammation Chemical compound Cobaltoxide Prostaglandine Stuffing Sense District Active site Reaction mechanism Hydroxyl Fever Acid Acylation Sodium hydroxide Cell (biology) Tandem-Reaktion Glycerin Controller (control theory) Aspirin Active site Beta sheet Process (computing) Setzen <Verfahrenstechnik> Agate Biodiesel Syndrome Cyclooxygenase Metabolic pathway Aspirin Covalent bond Soap Satellite DNA
Chain (unit) Prion Growth medium Operon Protein domain Set (abstract data type) Gene Chemistry Molecule Wine tasting descriptors Enzyme Machinability Tidal race Ribosome Protein Pharmaceutical drug Chemical structure Alkoholische Gärung Chemical compound Organic food Macromolecule Cell membrane Alum Surface science Protein biosynthesis Omega-6-Fettsäuren Walking Chemist Topicity Gene Multiprotein complex Chemical reaction Ion transporter Alcohol Anomalie <Medizin> Wine tasting descriptors Hydroxide Electronic cigarette Reducing agent Acid Azo coupling Chemical compound Pharmaceutics Freies Elektron Zunderbeständigkeit Stuffing Biomolecular structure Condensation Biosynthesis Ionenbindung Reaction mechanism Aldol Peptide Complication (medicine) Hydroxyl Wursthülle Acid Aromaticity Pyrogallol Aromaticity Condensation Protein C Cell (biology) Abbruchreaktion Hydrolysat Acetonitrile Open reading frame Magma Active site Elektronentransfer Sea level Boyle-Mariotte-Gesetz Process (computing) Oxide Atom probe Phase (waves) Antibiotic resistance Polyketide Precursor (chemistry) DNS-Synthese Gezeitenküste Carbon (fiber) Antibacterial Functional group Silencer (DNA) Chemical structure
Peptide Polyketide Ethylene-vinyl acetate Gene Stockfish Chemistry Molecular biology Biochemistry Machinability Infrastructure Protein Freies Elektron Chemical structure Active site Elektronentransfer Condensation reaction Pain Stereoselectivity
Alp (name) Ionenbindung Agar Aspartic acid Omega-6-Fettsäuren Omega-6-Fettsäuren Heterodimere Polyketide Gene Synthase Wursthülle Acid Erdrutsch Wine tasting descriptors Gemstone Chemical structure Thermoforming Gingerbread Baryte Fatty acid synthase
Sense District Heterodimere Omega-6-Fettsäuren Electron donor Synthase Wursthülle Acid River source Tidal race Protein Active site Elektronentransfer Fatty acid synthase Setzen <Verfahrenstechnik> Heterodimere Omega-6-Fettsäuren Polyketide Precursor (chemistry) Singulettzustand Multiprotein complex Electronic cigarette Freies Elektron Chemical structure Base (chemistry) Thermoforming
Area Heterodimere Omega-6-Fettsäuren Peptide Polyketide Precursor (chemistry) Protein domain Synthase Electronic cigarette River source Water Molecule Reducing agent Active site Chemical structure Exciter (effect) Fatty acid synthase
Deformation (mechanics) Precursor (chemistry) Steel Chemical plant Carbon (fiber) Topicity Wursthülle Multiprotein complex Coordination complex Alcohol Wine tasting descriptors Molecule Natural rubber Triterpene Cell (biology) Triterpene Chemical compound Polymer Synthetic rubber
Block (periodic table) Chemistry Alkene Triterpene Molecule Wine tasting descriptors Block (periodic table) Enzyme Isomer Pharmaceutical drug Chemical compound Nana (manga) Elimination reaction Cobble (geology) Redox Omega-6-Fettsäuren Octane rating Chemical property Walking Chemist Isopren Addition reaction Multiprotein complex River source Chemical reaction Erdrutsch Wine tasting descriptors Food additive Human body temperature Acid Stream gauge Multiprotein complex Origin of replication Phosphate Umami Chemical compound Cobaltoxide Hexamere Hydrocarbon Biomolecular structure Sense District Biosynthesis Peptide Geochemistry Wursthülle DNS-Synthese Deterrence (legal) Magnesium Controller (control theory) Orange juice Active site Beta sheet Sea level Polypropylene Chemical formula Phase (waves) Biosynthesis Reaktionsgleichung Precursor (chemistry) Malerfarbe Pyrogallol Menthol Carbon (fiber) Water Ice Organic food Triterpene Chemical structure
Lipogenese Sense District Enzyme inhibitor Biosynthesis Reaction mechanism High-mobility group Chemical bond Wursthülle Cholesterol Chemistry Chemical reaction Alkene Molecule Island Enzyme Ageing Isomer Hydrolysat Manganese Active site Acetyl-CoA Elimination reaction Sea level Setzen <Verfahrenstechnik> Enzyme inhibitor Reaction mechanism Biosynthesis Recreational drug use Precursor (chemistry) High-mobility group Formaldehyde Walking Molekulardynamik Coal Chemical reaction Cancer Alcohol Cholesterol Reducing agent Acid Chemical compound Carboxylierung Base (chemistry) HMG-CoA reductase Biomolecular structure Condensation Stuffing
Sense District Übergangszustand Ionenbindung Chain (unit) Reaction mechanism Aldol Chemical bond Geraniol Cave Wursthülle Quartz Chemistry Magnesium Molecule Meat analogue Enzyme Protein Ballistic trauma Precursor (chemistry) Active site Side chain River mouth Polypropylene Pyrophosphate Cyclische Verbindungen Chain (unit) Pilot experiment Biosynthesis Octane rating Precursor (chemistry) Walking Formaldehyde Carbon (fiber) Deep sea Chemical reaction Man page Water Acid Azo coupling Carboxylierung Ring strain
Residue (chemistry) Complication (medicine) Gene Wursthülle Aromaticity Magnesium Enzyme Phosphate Precursor (chemistry) Active site Cyclische Verbindungen Chain (unit) Potenz <Homöopathie> Polypeptidketten bindende Proteine Octane rating Precursor (chemistry) Walking Deep sea Katalase Chemical reaction Erdrutsch Food additive Acid Triterpene Iron Chemical compound Beta sheet Elimination reaction Pipette
Polypeptidketten bindende Proteine Triterpene Phosphate Walking Beta sheet Elimination reaction Chemical reaction Elimination reaction Soil
OK were bad I'm today really talking about calling the tide and there will be on 2 turkeys 1 such expert to cover a limited terpenes today and then finish up the discussion on Tuesday and then on Tuesday want to Chapter 9 to discuss themselves signaling and I small molecules and cell signaling connection that touch on the topic today last time we saw that factorize are quite headed genius and quite diverse that there is no war minor leaguers Zackariah component for protein that's encoded by DNA in some way rather we saw there was a sort of a random distribution of different on different structures really on the surface of the cell and this randomness is a key ally tribute and that affects the function right we discuss for example have a legal sack rides cause proteins that fold and so I'm having a you might imagine that having a diversity of different structures might also give you a range of different conformations access by the proteins known that letter letter remark is all that speculative but that's 1 of the ways that people are thinking about these things OK said so we also discussed household polysaccharides avidly take up water and if you're blowing your nose on the way into work this morning on the way into classes morning you definitely know about that we talked about mucus and nuisance and we talked a little bit about how icons are added 1 at a time that users that is making a couple points and but might have lost over to the elite like hands added 1 mother separated right at the time to build up to big structures and the end legal icons are added as complex branch of polysaccharides sometimes in other segments of 3 which we saw and sometimes even more complex after the synthesis of these and a like this I like him and there's lots of changes that take place through trimming by glycosylation it's feasible scissors that come along and step up part on like acidic wines and they do it in service any random fashion and that introduces additional diversity that further complicates our lives if we want a study these things but we also talked about how these oligopoly Sack writes exclusively found on the surface of the cell and there's very heterogeneous and composition so they're really go up like isolated proteins found inside the cell without looking for someone to prove me wrong on that 1 of his classes on watching this video and and that would be great for now Our dogma is that there are no polysaccharides that are attached to proteins found inside the cell rather this is sort of an exterior attributed that's some grafted onto proteins from the surface outside of the cell and we described this as a gumball model for the cell where the outside of the cell it is also suite with a lit with carbohydrates and then the inside is chock-full of proteins and DNA work on balls of course have gelatin as the protein then we discuss how to much too much with too much focus too many gum balls at least approaching cross-linking and information and how this leads to diseases like diabetes etc. and how these are really unavoidable consequences of Western diet that we have such high concentrations of carbohydrates that on it's kind of inevitable that we end up with some inflation resulting from this sort of thing and said this is 1 of the major challenges I think going forward is now to apply this knowledge about chemical biology about the underlying mechanisms that are taking place at the level of Adams bonds and tried to convince other people in the country to to change their lifestyle really that's not that's a nontrivial challenge the challenge of asserted next era which is going from and bonds going to society that's really a major ugly that I leave to you to to take a rights on withering questions about what we saw last time about carbohydrates about like asides anything you wanna know about carbohydrates and I will endeavor to answer and I know everything my best stop the champ yet yeah OK so case the question we repeat the classification in here are the question was you discuss those sugar substitutes and on some of the sugar substitutes linked to other diseases a peso all it's your question a moment but before you and I think you raise a really good point that sugar substitutes that I presented to and compounds like the thing isolated from steadier sucralose etc. and those are at a panacea they're not completely benign and 1 of the astounding things that we find is that the sugar substitutes even the other nite digested another not directly produce calories and do seem to result in caloric intake by animals were fed the sugar substitute and spend an hour theory best under best guess of what's going on is that there's actually sweet receptors not just on your talk but also that far in Europe in your stomach they're kind engaging what kind of food is present and when the sweet receptors get stimulated by sugar substitutes they sort of actively started taking up a lot more calories than they otherwise would be be and said no and yes even soft-drink might be 0 calories and it has the effect of stimulating you take up more calories than you otherwise take up because you expect your your body function is expecting something sweet and sugary a case so that's 1 aspect of what's going on you use this is no free lunch basically taking out a 2nd aspect is on the linkage to cancer and I'll be honest I don't know very much about that about the you know the latest research on that sort of thing and I think there was this kind of a history with the leaders in that context and some of those kind of early on technology like 1878 kind of trials were not done with the kind of rigor that we reduce today so I think it's time to go back and re-evaluate our thinking about that sort of thing using different standards that we know applied suffer example those involved really high concentrations of sugar substitutes were exist physiologically unrealistic although I don't know people change leaders upon leaders of diet was offering so maybe that is actually so maybe someone could decide the experiment designed the experiments needs to go back and look at it more closely and that's all I have to say about them but they stressed that other questions anything you want about carbohydrates of satellites polysaccharides came that OK thanks for asking that it requested an action of Union time OK said ties question is and how fast to the minor separates it added and on answers really fast like these are being added on the subsection timescale so underwater like Ms these these reactions are happening very quickly .period nicely enzyme catalyzed and on the reactions are we are not slow this is a really fast reactions so I think your question would be really interesting want to compare against say DNA being added originate conversations and I don't have exact numbers that and I think that's a great deal of food for thought questions trusted other questions yeah it and that's for sure and and we last left off last time we were talking about polysaccharides first-rate polysaccharides butter beans and I just give me a moment to find out where we left off and the most start again 1 moment right so I showed you the fatty acids in days as kind of our final thought and I I think maybe 1 the is start their pay so we saw that the fatty acids and bases was really complex machine that allows the synthesis of that and it does this on by having this robot arm that cycles around OK pay and we saw that the reaction here which was this this squeezing
condensation reaction where it's basically an Algol that involves the fire Wester of paying out and take a look at this reaction really closely because I wouldn't have a quiz about this I want you to build the review this reaction for being so please look at this market moving on but at the very last that I
kind of glossed over this reaction but it's a really interesting 1 and I want to take a moment to appreciate this so that we discussed how the robot arm that moved the intermediates amongst the various enzyme domains was late to the intermediates through it by Westar and that was that also spent the final arm that I showed you and so the very last that is this fire West erased that has to hide realized this fire last year and it's really actually notable essentially fascinating and a great great place of converted evolution of past of our evolutionary borrowing that at mechanism for this hydrolysis borrows very heavily branded cereal producers down to the point where it has active site series and active-site history and active site as hospital osmotic asset and that's really notable and I think it really fun because and that gives us a very rapid way of idolizing these viruses over here all the way down to a carboxyl gasses and what's great is that we don't really have to learn some new mechanism and this is just something as totally familiar to us OK so I want to talk to you about what happens next so I showed you how these things are synthesized I want to talk to you next about how they're applied in the cell and how the fight itself signaling so let's start with what they're used for
primarily so these fatty acids formed the barrier on the cell surface they their what's composing the plasma membrane and I want you recall that the plasma membrane is this layer upon that divides the exterior cellular exit extracellular about you up here from the cytoplasm down here and in this area is pretty impermeable and actually it's really super hydrophobic over here there some affiliate functionalities that interface between the water and the hydrophobic stuff over here and all of that will look at the structure of a moment but on the fact here is that the cell very tightly controls what's going to be allowed to pass through its into its interior into its cytoplasm but with 1 major exception that major exception is of course pharmaceuticals writes a small molecule drugs at a height of that are going to be readily able to slip through this study impermeable barrier was otherwise impermeable barrier OK so all of these compounds in here all of these treaties in Europe fatty acids that cemented take a closer look OK so when we look at the composition of the plasma membrane Spellman human cells what we find is no surprise chemical heterogeneity OK we find diversity we find that there are a number of different molecules and I can just give you some percentages of those molecules over here has said these are average percentages over here and you can see that the plasma membrane is composed of a diverse array all of these different forms of these different molecule of these different lipids OK and the effect here is on different changes in the base custody of the plasma membrane and we find that there are areas of the plasma membrane they're a good deal less viscous than others that are less fluid than others that are more viscous than other areas but these are regions that are sometimes called lipid rafts where there's even in areas where the lipids themselves are on insoluble in solvents like acetone you know can take up that the cell and usually all this stuff goes neatly into organic solids like Gaston under some regions that refuse that kind of treatment OK so I do in other cities arranges of different percentages and they range pretty broadly in those regions have important consequences in terms of the fluidity of the membrane In the model that you might have learned of Back in high school the fluid mosaic model of the of the cell and is true to a certain extent but none were finding is less fluid that is actually regions of real density on the cell surface OK now here's the thing in order to change to signal things inside the cell in order to affect us cell function and there's a series of enzymes called possible like cases that play a key role in the cell by high July saying the lipids that I showed on the previous life so they go through and their high July the testers Saudi-sponsored in particular spaces where it in particular places where each enzyme has a particular specificity for specific Esther for example and on the consequences here are really fascinating this has the effect of altering our cell function by providing molecules that and then buying 2 sets to 1 proteins and also by and altering an old very local looks to a local except on the composition of the membranes that are close to membrane-bound proteins OK
so that's so we're starting to see that that its play important roles in cell signaling and I also want to talk to you about cell to cell signaling understand this slide over here and this is an example of lipids playing the role of the cells signaling with inside the cell and now I want to talk to you about how cells talk to each other a case so there are many different modes of cell-cell communication many of them involve the real communication that touch the cell to cell contact that we discussed earlier in this class on but there also ways for cells to secrete lipid based molecules that then go off and on single other cells together on activities pay to get in on the action and the B
share you'd example of That's so platelets cells release this X A 2 should of and that's really slightly less and that amplifies clot formation so TSA to its supersize from a compound called rapid on a gas at Wallstreet structure or economic in a moment long story short you get this compound here that is derived from fatty acids and and this has the effect of signaling other platelets to start at the start of declining to initiate fire and also to initiate its move to get smooth muscle to relax in the area to encourage blood flow into the region OK so small molecules are providing important signaling molecules for cell function but it turns out this is
actually very complex of Panama going to disclose over encourage you to read more about it in the book and it's actually fascinating topic and affected devote a whole lectured nothing but this is it this this sort of cell to cell communication involving the use of the could try and I costs noise is actually a remarkable so what I'm sure you here all are a series of different compounds that are synthesized by various enzymes shown in blue so each 1 of these blue era as is an enzyme catalyzed transformation and will take a look just 1 example of this so for example this look trying 1 has an epoxy either pop side of course is a terrific electrified and in concert with looted by this up this pox on I can be nucleophilic we attacked by that by all From the glue declined to give you this conjugate that now has a bye week the bond despite weak that this compound here and keeps going until it gets is that the trying 84 which is then used to stimulate leukocytes under Ronald sells etc. and in the supportively bronchial and vascular smooth muscle in the long and so on whether that what we're seeing what I'm trying to show you is a cell signaling cascade that eventually leads to inflammation in the lungs and asthmatic response this is what happens when you feel your and your lungs tightening up because you can't breathe anymore when you're getting in an allergic attack or an asthmatic attack on what's happening in all of the signaling molecules are implicated and so underscored mates by having lots of signaling molecules running around this correlates the response of very diverse cell types ranging from neurons to macrophages and it's absolutely essential that you coordinate the state's right you wouldn't want for example and the body of cells contracting and you know constricting and unless you had other cells that can that and you know redouble efforts to to try to the deal with whatever it is that's causing their pain bright you want the macrophages the Interlachen too but you apart and recognize whatever it is that's causing that you know that the cells to attract OK so they are all are of many different classes the of the site concentrates they all share of Ivory Coast common core this erected on a gas it over here and note that this is simply fatty-acid this is missus if this can be synthesized using exactly the Polly the Tyson case that I showed earlier the fatty acids that face showed earlier that 1 of the robot arm that moves back and forth between the different subdomains OK let's
take a closer look at a rapid Dodik acid so the 1st step in the modification of a rapid gas is absolutely fascinated fascinating there's a class of enzymes called cycle oxygenates that add oxygen across this these 2 double bonds to give you this prostaglandin molecules that and this is the very 1st steps in all of the cascades that I've been discussing with you the very 1st step here is this oxygen be honored by catalyzed by 2 different inside Cyclops today's was and Cox to their abbreviated COX Cox and on all of these are so once this thing is synthesized there's a whole bunch of other enzymes that can lead to inflammation OK so pathways like these go down to lots of different cell types down here and start stimulating and information so if we can
block this step up here then we have a very effective way of dealing with information and by the way by inclination I mean Beaver I mean you know swelling I mean like you know the immune system started to spiral out of control of pages you know walloping on whatever's because your by including itself prepared and that's about it and so on for over a century humans have been using aspirin as a way to combat in this this pathway after for it turns out is a covalent inhibitor of on-site in today's 1 and 2 it's fairly nonspecific and we zoom in on the sidewalks today's active-site heroes active-site over here this is elected on a gas adults active site and in this Red Stick model right here and is a series hydroxyl that's found in active site this series hydroxyl is acetylated by aspirin so that aspirin trams satellites it transfers the Esther from the aspirin answer to the cycle oxygenates disaster from this side to beside you can imagine this is a very easy reaction very facile very low-energy analogous to all the trains as to reactions that we saw on Tuesday right on Tuesday was showing all that by Leicester exchange reactions right this is totally analogous to that you eat that aspirin that spring readily flows through your whole body geared up literally minutes flowing readily through yourself membranes because it's hydrophobic enough and then when it reaches its active site it starts attacking the hydroxyl and covalently satellites that has the effect of shutting down this pathway over here and doing so prevents the cells from from responding by inflammation of symptoms as that shuts down very quickly be the fever or whatever it is that you're dealing with that makes sense Henry's Beta said Ron Arad and so this notion that is actually covalent inhibitor is a relatively new 1 I think I was discovered maybe 2 decades ago or something like that and said no and at site the molecular mechanism underlying its covalent relatively new and actually fascinated it's actually still pointing this out because it's actually very hard to get molecules that Kobe only modified targets in the cell was approved by the Food and Drug Administration medicinal chemists in general are leery of compounds that form covalent bonds with targets and the reasoning is on some misplaced fear of allergen city of this city is a worry that you're going to modify itself proteins and that in turn will stimulate the immune response and on to those who say that I was .period aspirin as a prime example of why that's not such a big concern now having said that there is a small percentage of the population that has something I think all Rex syndrome and there must be 1 person hearing about 100 people this class anyone is allergic to aspirin it would be about 1 per cent in the population said and those people allergic to aspirin actually have you know stimulated immune response by this code to the covalent added or perhaps another covey OK so lipids in fact of course played a key role in our everyday lives as soaps said so all the leopards and that they should be on plaza membrane slide and can be high July quite readily I'm using catalytic amounts of sodium hydroxide this is typically lie it l II and this upon application reaction is something that humans have been doing for millennia really and most notably of course by the time protagonists of Fight Club crew slashed entire Taggart and antagonists by close to use excess of lipids from liposuction to make really high and soaps for boutiques but I have to love that will be if you see the movie check out the my cost the at the very end opening credits it's pretty awesome if you haven't seen this movie you should see it just for those upon applications in 1 of the that and here's an old-timey picture showing that you know how that historically this process to place so when you do this you can isolate out depending on how you do if you do this in the presence of ethanol you can isolate out and esters fatty acid esters that basically are nothing more than biodiesel this is stuff that you can put in the time of your biodiesel Mercedes-Benz and use it to drive around the campus and the other thing that's isolated from this is glycerin which is a very valuable commodity items it's used I'm pretty extensively as moisturizing soap and I'm actually the glycerin soaps or slightly better than the fatty acids so when you have twice as the city hydroxide no ethanol of a fatty acids Nunavut 2 kinds of so really and the glycerin soap to wash away a little bit better than the fatty acid soaps and a slightly more moisturizer the right of that city I think that's all I have to say about facts and weapons and tell if you have any questions about of exotic no you ever wanted to know about that but were afraid to ask but what about cellulite an inevitable consequence of being human don't panic
director and diversification so I went to 6 years now and I want to talk to you about other kinds of polypeptides would showing you the simple ones but it turns out this is amazingly rich class of compounds this class of molecules extends to all kinds of different antibiotics and all kinds of different circumstances and some of these have nice bitter flavors like this hot constituents and others as you know we just don't you know really what they do but we could find all kinds of examples so 1 way diversifying is have hydroxide in the you know the sort of these mutilated in the structure means the loss of the structure and that sets you up very neatly for our Latin this molecule here so this is the way that we can start with straight chain precursors and get to rain OK this is a very simple way of getting to race right we have electrify all which is the filer struck here we had a nucleophile which hydroxide and note that this even those that in all it's not attacking like any all it's actually attack its uniformity in all Leicester and a note to the compound that results from 0 OK so as to sets you up very neatly for attack users is perfectly poised on the way in terms of distances nucleophile and electrify appear very beautiful chemistry so this is going to set us up to make a really complex the parity for complexity brace yourself and here's what can happen what can happen is you can get to these aromatic compounds that I alluded to at the very beginning of this discussion apology fights and on all you do is you simply stop the straight chain precursors that have deals on recall that this is 1 of the products and Brondby the the of the sequence that I showed what we talked about that acid synthesis and I showed that it was very quickly this intermediate was very quickly reduced by any BPH but here it doesn't go on to the media reduction instead this on this he turned things around and it sets you up for an outdoor condensation my all-time favorite reaction the beautiful although all object of wonder because a reaction wonder because it has such an effective job of making carbon-carbon bonds because this is a really classic reaction of a major challenge however is these Polly the term things are ridiculously reacted I mean you can't really readily isolate them so well unless you could freeze and benzene and I work with them and action ecology does that that there really nontrivial to work with the Empoli key terms are so desperate to do this although reaction this everything is so nicely set up users Getafe on this beautiful six-member braved in intramolecular fashion that these are far too reactive to really work well and it's remarkable that cell has evolved mechanisms to work with these intermediates so at the attribute of this class of enzymes is that they can have these intermediates kind of pop around the cell and by looking for the next active-site rather everything has to be tightly held in place the intermediate has to move from 1 spot to the next spot to the next spot and it can have time to flap around and start making random things OK so here's what can result and this is the thing that really blows me away the UN number of molecules the result is a really astonishing in its diversity in its complexity and its sheer chemical beauty and these things are really are wondrous molecules Texas I 1 is a very effective antibiotic I believe we talked about it that in the context of ribosome will protein synthesis and these are cafeteria another effective in about this 1 1 slope wars in the cell membrane benefactors traded at 50 of the 2 thousand or so approved pharmaceuticals are directly Polly he tied up and probably another couple hundred or so are derived from Pollack the tides so these are synthesized on a massive scale not buy organic synthesis rather they are isolated through fermentation by microorganisms and the microorganisms are like little factories that with these things out in the incredibly valuable write something like Tetris cycling is sold and probably in the town level for a year and is used quite extensively within a given in the little italics that actually tells you what organism this be isolated problem so each 1 of these compounds is synthesized by different microorganism now you can imagine it takes a microorganism a lot of time and energy to make these compounds so why why do you think it is that the microorganism is doing that why would a microorganism wanna kill so why would the microorganism want to synthesize compounds they're gonna kill microorganisms with that have again so the competition for scarce resources these microorganisms are fighting chemical warfare against each other and there is this constant arms race to try and develop better chemical compounds that will kill off their competitors if they succeed they wiped out all the competitors and have the field free to themselves they chew on all the tasty stuff that surrounds the problem there is that their competitors are
also developing ways to nullified and neutralize these compounds and so these competitors are really really good and I think we've seen 1 example of that Texas site 1 can be readily pumped out of the cell and so the competitor microorganisms developed these big pumps that sit at the cell surface and Bernie and operate nite and day to grab onto Texas and other molecules like this said simply expel those molecules from the inside to the outside of the cell and on the other strategies that we see the earlier in terms of antibiotic resistance but it's a constant cat-and-mouse game between the microorganism that's trying to compete and the other microorganisms that are trying not to get killed so that we can have our spectators watching from the sidelines of this ongoing multi-million-euro war this is an endless war it's a war that's been going on longer than humans have been on this planet and on this fascinates us and gives us all kinds of opportunities to control the pestilence bugs that afflict us as well and so on we do things like row these things in large quantities and then use them to kill off the bacteria that the us yet at the same time of course word knowing full well that were highly dependent upon other bacteria that have a symbiotic relationship to work with us and are of affected by these compounds equally irate and little off topic I I love this topic so forgive me if I would get back to what we want to talk about today I would talk to you about this synthesis of complex molecules like this and I didn't is a lot of what we've already seen in terms of fatty acids and this applies to you are much more complicated Pollack key tights and faces and so on let's talk about how the rectum Isidore synthesized so refer mice and it's a very common antibiotics it's use I believe some time for treating acne you might have encountered at some point is used for all kinds of things it's a prefect Ivanovo on how was it synthesize it synthesized ban on large exercise by 3 large macromolecules macromolecular machines OK and these machines are organized in the order of action along the assembly line for this molecule OK so again there's 3 open reading frames where open reading frame refers to a single gene that's encoded at the DNA level translated our side transcribed into our model and then translated as 1 contiguous protein C have 3 of these are lined up each 1 of these letters tells us about the identity of the different active site domain so different enzyme active-site made up here repay and said a lot of these are familiar to us this is a sole carrier protein ACT this is the 1 which attaches the case probe medial and starting material to inspire Lester the possible cost-effective ideal robot arm and then the next step is a key test phases so that there's a pleasing condensation next step over here is on a peaceful transfer is that's going to then transfer the at the intermediate to some other on file aikido reductase which seemed covered up days on another it's transfers that this gets transferred over to the security and then again another Clayson another it'll transferees Ikeda reductase etc. and so the product from each of these over here here's the aren't yesterday's here is the product of the Clayson after the reductions that takes place next on another key days etc. to the easel carrier protein and so each 1 of these Peterson faces along Gates thing by 3 provinces it introduces a new parochial fragments and then each Niketown reductase gives us a new hydroxyl and note as usual the exterior chemistry of that hydroxyl is rigidly controlled of pay and Long Story Short at the very end over here the last step is is carried out by the Silas trees that's actually rather than doing a conventional hydrolysis of the silencer it has the hydroxide the terminal hydroxide ,comma loopy and and we over here to attack this Carbondale this electrical revealed by Westar and you can imagine this active-site bending the US the intermediate structure to position this hydroxide right up close to this Elektra filet carbon I'm beautiful chemistry on the beefier after this is synthesized by this these polypeptides says things are passed off to a series of tailoring and sites that they get in on the action these include people were 50 or a threat of theory and this is similar to cytochrome P 4 deity that we talked about earlier the class this is an oxidation an effective enzyme for oxidizing faith and this case is going to be oxidizing beside tertiary carbon right here to give us a tertiary alcohol and then there's a bunch of other enzymes that appeared on some carbohydrate functionality and then the whole thing is quickly pumped out of the cell because a cell doesn't want this very dangerous antibiotic hanging around the case of the cell is a complicated machines at the end of it there's a mechanism that's actually not that will define that kind of sweeps of the product and scooted out the door before it has time to wreck havoc on the interior of the cell let's take a
look at the actual arms he told police he tied there's this is from a structure that was solved by my colleague Charles side in the chemistry molecular biology biochemistry department sureties your right and I she did this when she was a stock and it's really 1 of my favorite structures of all times that I have a lot of the infrastructure of the little visibility OK so in the very center of this is the easel carrier protein OK big-picture 1st what we're looking at is we're looking at 1 of these on polypeptides today's machines that I showed earlier on a previous
life so over here recalled that I showed that there are 3 of these and after you have the only together in a moment but each 1 of these
is arranged in this in the structure of a doughnut pain and in the very center is the easel carrier protein with the fossil pent up buying that thing going to swivel between each 1 of these subunits OK we now don't think it's entirely a selection of slower more complicated but I think that's a good model for us years so at the 1st intermediate the robot arm comes over here to the covered up days over here I think the Quezon condensation reaction is on fears of catalyzed and then it goes up the peaceful transfer and then and then over to you decades outside I got this wrong he tells his face at the top of the sole transferees anarchy 200 updates and then by it's paid so these arms being machines are arranged kind of the way you would arrange the perfect assembly line so that everything is right there and intermediate just between the different active sites this is a thing of beauty isn't so check this out
and this is the fatty acid us in case I showed up for up earlier and it turns out that these form dimers and on I'm showing you this because I want to talk to you about how the arrangement of the
stone actually things into bigger assemblies OK so
Over here I said that there were 3 of these doughnuts turns out that these doughnuts are actually diners
before I show you that I need to show you that in fact actually I need to show you that this dimerization as president and so this is a fatty acid said that since there show that earlier at the the very 1st slide of today's lecture in 1 way neglected to tell you without actually this forms and the diaper where 1 of fatty acid synthesize on this side and different body after the synthesized on other side so in similar fashion owned by the way the structure was solved by netted bonds in similar fashion it and it kind of looks like a gingerbread Regnier right panel it's like into preventing the feet down here arms has won in and this is the narrow waist anyway in a similar fashion the arrangement of these
doughnuts is also in dimer form OK so check this out OK so here's
1 donor over here this is this is module 1 up here this is module to Model 3 and so what's actually happening is that this is actually a diameter of 2 assembly lines that are not together in double-helix fashion and on this 1 in blue is synthesizing 1 colleague he tired and this 1 in red is synthesizing the same polypeptide but in parallel OK so in other words the assembly lines that make these complex chemical structures are actually I'm running all the time and there's multiple assembly lines that are identical they're running right alongside each other so this is kind of like going to analyze the factory or something and finding it's not just 1 of the assembly line on the floor but 2 assembly lines that are moving in parallel to each other and both producing the same car at the variant case out again this is the OK so again both of the types of faces and fatty acids and bases are diners on this 1 being a circular diner and this 1 being ahead detail and when things moved through the polling the types of the intermediates procedure on this in unidirectional fashion so they're starting up here moving down here moving down your moving down here and they're headed off by all sole transfer races OK which then transfers the intermediate to the next missile carrier protein which and takes it down to the next owner of pay and then and you end up with this complicated refer mice and over here Our are Rice's precursor over here the on fatty acids and bases as we discussed however rather rather than getting things off instead the scene intermediate keeps popping between each 1 of those different active sites and fact the intermediate cycles through 7 times until you end up with this long chain fatty acid and the very end evidently if falls off because there's no more room for 2 experienced players run out of place in active site can make sense they can all draw diagrams described how this works and you even make some predictions about that sort of thing we could see other 3 powerful Wright said
I went to securities that pay 0 0 before doing any
questions about polypeptides anything you wanna know the polypeptides that topic OK and yet just think this is yeah yes to molecules of this erythematosus precursor yeah and you know OK I can resist there's so much water tell you but that's the 1 of the 1 of the really cool areas in this research in this area is to start moving around these on active site domains so that in the end you end up programming a different structure you might imagine setting this thing up so that instead of doing a reduction made you end up with the Quito over here instead and so on this is a really active and very exciting area of research the parity of its
move on I wanna talk to you about a different class of small molecules that a synthesized and by cells
and on the certainties of molecules called terpenes these are all built from 5 carbon precursors of these are familiar faces a juror to rally all for example has that kind of spicy wonderful flavor of ginger rateable tried that at some point but these are things that are really familiar to us Polly I Supreme is natural rubber right that's actually isolated from the use rubber plants and hand out all of these have built up from 5 carbon precursors let us go ahead accounts and carbon steel case so we're going to have 1 2 3 4 5 and then notice that there's a red right here that red line is going to be joining together these 5 Carbon Building Blocks N N N and these can be strung together in a very long polymer right so in any have I Sabrina's Supry Tysabri and then a very very long polymer that has that wonderful stretch field that's a natural rubber has been so I would say I have to introduce you to some important nomenclature and we're going to call the seat and precursors during a during third-year Girardi also arterial and never going to call the see 50 precursors that's 3 i Supremes Bonesteel or upon solids alcohol and then there's see 20 precursors were going to call during on alcohol so see 20 is likely to see tens put together hence the name during your journey of pay and I'm going to be using that because it turns out that these are the precursors to much more complex compounds so totally analogous to what I was discussing what talking apology ties where we start with these kind of simple linear compounds Turkey's start Lydia starts simple and then like origami become amazingly complex and that complexity is going to be really great topic for us to discuss a ride on me show
you are and where we're going with the complexity so that the taught these are street she precursors that I showed him the previous slide charity across a he'll a journey ulterior Perot phosphate and these again are synthesized from 5 carbon building blocks 2 building blocks ice painting terrified environmental alipay-a prostate all show you those 2 in in closer detail in a moment so but suspend for a moment where they come from these guys over here illustrates the change the current precursors can be folded up by a class of enzymes known as terpenes said basis for Turpin site places and net fact is you get out these very complex skeletons of really complicated molecules of cases for example this is the skeleton that eventually will become tax down here tax all results from a series of tailoring enzymes that oxidize various carbons in this this tax a dying framework and then depend on things like this 1 the little short peptide fragments that have tied Frank Caso you start off simple you start off Libya and then you get increasingly bold things up the cycle eyes and the new modified after cycle was OK and what's great about this is that follows the same formula that I gave you all we talked about the fatty acids you start simple start to current regarding building blocks you build linear things and then use idolizes and then you get more complicated the exact same formula here except now we're going to build everything out of hydrocarbons this can be very few oxygen so 1 0 and by the way he's familiar compounds as well but like many in this is isolated and I think I see this isolation right From my orange peel needed the backing 1051 a something like that of 50 would-be lover and yet so this is the content you isolated but you learn how to how we set this Alice's synthesized myself but it can also be oxidized to give menthol and nice whichagreed kind of taste and nice and meaty taste on this and prepare for a dying is modified to make our team as soon as this is a compound that has supported anti-malarial properties and is extremely useful therapeutically I it's him this is kind of a big picture everyone with me so far right at the balance of looking at the nuts and bolts no more big-picture
site on the enzymes that make the debt to the cycle station head of remarkable remarkable chemical specificity OK so starting from the same precursor different Turkey thoughts in phases and direct the synthesis of different stereo isomers of this bicycle compound and then other terpenes investors can direct whether or not you get Spiro few strings this is views remain went to rings are joined at a quarter carbon that's called Spiro views of these called Unisys a transfused and you really get monster rates so whether or not you get a 5 7 and 4 6 6 ring or a larger rings is all controlled by the centerpiece of faces and they're really really good at what they do OK so this is their controlling stereo chemistry and we geochemistry in water at room temperature OK every talked about whether there's a lot of other complex terpenes I can show you exactly Pasadena class of molecules and there's targets for synthesis etc. This talk about how they're put together starting at the most basic level down here so I told you that all of these are synthesized from 5 carbon building blocks that are going to be I Supremes in the Finnish structure OK when I Supreme is this compound here the 5 carbons with the carbon-carbon double bonds in the middle OK what happens it is but there's a someone starting material is Diamondville Allah this has been a on when they are a little like Pyro phosphate as its leading grip and no surprise the active site that's going to Palace's reaction has of course a magnesium available to act as a Lewis acid and stabilize the Piura phosphate making a good living grip in the product here is going to be old for stable a little late cobble Carolina OK so what happens there's 1 dealer ,comma apparent warrants this conform resident structures hence stability the resident structure can and that started tertiary corrupt I'm on but itself and awaits the tertiary cover can and is held away From the incoming nucleophilic I suppose ISO Centeno Piura phosphate this compound here and on this sets you up for a nucleophilic attack which then gives you a new tertiary cover character and then in the final step of beta elimination step gives you in the and this during Altai Foster and then you can imagine this could be the starting material for additional by the keys to be added on using exactly the same chemistry that I'm sure you hear it makes sense parrots and let's take a closer look right so and it turns out that
these things synthesized using reactions that you know completely understandable so on stepping back and show you how to synthesize and these are compounds down here IPP and Diamondville prostate 1st these 2 can result from a simple isomerization right that's this carbon-carbon double bond over here getting around by sunrise to form a more stable and more substituted band of dynamical Allah pirate foster care and there's an enzyme that analyzes that reaction and the active site looks like this it has a on it has a menu manganese and maybe hasn't manganese ions that informal Lewis acid relationship with the we glutamate inactive site and this can act as a base to catalyze the secret got to do supranational here and then there's a nearby by all that acts as a as a acid to predict that I'm resulted Carter the results the resulting Caribbean island as this thing gets the president OK let's start at the beginning "quotation mark everyone this continously reaction down here make sense of it so let's talk about how so if we can get to hear then we can get to know how we get to this he I think he is synthesized using more or less the same sort of chemistry that I've shown you previously In the context of fatty acid synthesis OK it's basically going to be set up using on a series of Quezon and condensation the case all carbon-carbon warming events are going to use the long reaction and there's an enzyme called agency Coale said taste that's going to synthesize this agency Kuwait molecule over here from HMG CoA you can then rarely gets to this compound here using Australasian from 18 and then answered hide Esther reduce the size that idolizes Esther and reduce counted alcohol and then ATP then transfers Piura prostate to the primary alcohol and then you can do and elimination reactions I said Brent is I'm idea carboxyl Asian and then elimination of alcohol and the city wherever the context for resource reaction like this on Tuesday we've seen the mechanism of this reaction before you recall what we saw on Tuesday the carboxyl issued giving us in during the late From was the was the sequence told why why did we do that yes we did this the carboxyl ation right and that it was simulated and that was the late news for Du member it was the claims and rights so this is being done by the Towson State France is poorly analogous chemistry is nothing new here thanks from you rescued us OK but then there is the figures this reaction over here will never wanted Cassidy's synthesized so here's the reduction here by HMG CoA adopted this level like acid then becomes a precursor for the eventual synthesis of cholesterol so if you could shut down this step or this that you have a way of preventing the formation of cholesterol and actually is pharmaceutical
a a very important reaction this is a reaction that it is very extensively inhibited so HMG CoA reductase inhibitors include compounds like little or no medical or etc. and immediately start to look a little bit like that never like gas rights of this compound here is kind of like a folded up never won acid and then up here you can imagine hydrolysis of this lacked will give you something it looks a little bit like medal like acid as well so these compounds are very widely prescribed it's literally billions upon billions of dollars a year of the stuff is sold and probably everyone you know over the age of 50 years on 1 of these compounds because they're so effective at suppressing the formation of cholesterol and that seems to have such positive benefits for cardiovascular health and also even on some into cancer abilities as well so you know these are remarkable compounds they've changed how we treat patients and other sold an enormous volumes OK and again these things look like the product so they work as product so Ivory show
you how to connect up the the the eyes of units and 1 thing I need to point out is that this is the example of a very rare not only although all carbon-carbon bond forming reaction but this is not very typical and that Mexico special OK right
last mechanism of that at this 1 of blows me away there's a class of that the next step here is to take this straight chain precursor and then folded up into some semblance of the ratings and then it's cycle life thinks so the class of enzymes that does this again a culture of peace and faces and I'm here is 1 example of this ,comma of a protein called a resolute she said there's this starts with Bonesteel of Piura phosphate the way this works is that the enzyme has a very deep active-site it's kind of like a decayed OK so deep deep at site that's shown here right here at the mouth of the cave this is actually a transition state analog a product analog that our sorry substrate analogs that the enzyme cannot act upon so when the crystallization took place this shows us where the active site it's again and again that the site is this really decays now at the tips of my fingers Over here there's a series of carboxyl experienced side chains back and then kill a man magnesium pilots OK those magnesium ions as you might expect formal Lewis acid relationship with the Piura prospect analogous to what we saw a couple slides ago similar chemistry the fact there is that this was the mouth of the cave shot in the arm magnesium scum down and the Piura prostate gets and gets a coordinated to those magnesium and that was the case shot now the at interior of the case of the kind of the backside in here is highly hydrophobic this makes sense right the molecule that half the byline is very hydrophobic has 15 carbons so this side over here it's going to be at the mouth of the cave binding to the magnesium ions is is really nicely and then decide over here is hydrophobic so what happens is as the key shots all of the water in the cave gets squeezed out it's all the water gets pushed out this will be critical in a moment and I'll tell you why that is the 2nd time now OK so we
the finding by the Bonesteel power phosphate the 2nd step here is in the active site the active site is shaped a note in such a way that they see 15 pieces is pushed into some semblance of the cracked product so the 1 enzyme over here that's going to be supersizing Arista low gene will have
a on they are active site that shapes to push this straight precursor into these 2 rates but the 1 that's going to be synthesizing say this spiral fuse rain is going to start the same starting material but in this case is going to be pushing the other Bonesteel into something that looks like that 10 the next step here is on again clampdown died last April the 2 magnesium ions and push out the the magnesium ions again actors Lewis acids and they trigger the deep pass correlation reaction the stabilized the Piura prostate leading grid allowing it to take off and that has the effect of triggering a combo can site was Asians that eventually leads you down to 1 and only 1 product like this 1 now the complicated thing here is that this comic has stabilization is not some simple 1 stepper this is a really complicated reaction of show you what looks like on an upcoming slide but involves multiple steps and involves a requirement to stabilize cover Palin's preferentially cover had and intermediate preferentially and so the enzyme has evolved this active site that has for example aromatic residues position neatly over public had to stabilizes ,comma countenanced by cat iron pipe interactions the same interactions that we saw very early in this course when we talked about non-covalent binding in addition to many of these compounds many of these compounds are synthesized through other intermediates and active site has ways of actually then catalyzing reactions on those intermediate compounds as well and then the
final step of course is the bait elimination to produce the product and this is analogous to the elimination of some earlier to where there on the up Bonesteel part of prostate was synthesized through elimination reaction this is that same steps OK so these are truly wondrous reactions and 2 of them these are things that we can talk about quite a bit and I would love to talk to you about them some more but
I actually won reward all of you have shown up today but with a very very short and easy quiz so I'm going to stop here actually so I'm pleased takeout Ohashi to paper and other get ready for requests


  713 ms - page object


AV-Portal 3.21.3 (19e43a18c8aa08bcbdf3e35b975c18acb737c630)