Lecture 15. Glycobiology & Polyketides.


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Lecture 15. Glycobiology & Polyketides.
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Lec 15. Introduction to Chemical Biology -- Glycobiology & Polyketides -- Part 1
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Weiss, Gregory Alan
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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: 0:00:19 Carbohydrates 0:03:15 Glycosylated Proteins 0:07:25 Extending Oligosaccharides one Monomer at a Time 0:08:26 More Knee Join Oligosacchardies 0:10:25 Snot and Mucus: Anionic Polysaccharides 0:13:21 N-Linked Glycosides: Added as Complex Oligosaccharides 0:22:56 What is the Function of Glycosylation? 0:25:37 Cell Culture Production of Proteins 0:27:54 Glucoronidation Used to Designate Small Molecules for Excretion 0:29:49 Glucose Homeostasis 0:31:39 Non-Enzymatic Glycosylation 0:35:29 Sweetners: Tase Good for the Calories 0:41:00 Terpenes and Polyketides 0:45:09 Nature Prefers Thioesters for the Claisen 0:48:06 Rapid Exchange of Thioesters 0:49:28 Fatty Acid Synthesis by Polyketide
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but it's a very briefly the review what we saw last time before we go on to some new stuff and less time we're seeing that in the human body is really only 9 months after rides that bound by their use in carbohydrate chemistry and this is kind of astonishing because if you think about it there really could be in infinite number of ways of eradicating carbon center hydrated or rates a carbon which is chemical definition of carbohydrates but there's only 9 at the center town and we talked very briefly about an America that I don't think this is such a big deal so I'm not going to honor it and we talked of a more extensively this is actually important that carbohydrates in a converted between heavy acid Taliban and al the hierarchy to inform and that the Haida Keaton form is reactive that's the form that has elected pile that can start reacting with surface proteins in your Europe cells and then cause of eventually advanced glycosylation and products that will talk about today and then I we talk .period we also talked about the hot sodium and not alliance these are our key ionic intermediates that our our youth that are observed when you either formal or break like city bonds and and we talked at the very end battling sack rides things like starch that a long strings of carbohydrates that strung together by a considered bonds OK today I want to talk to you about complexity and about legal Sacca abouts polysaccharides that are good deal more complex so all legal Sakharov arrives on our and were going to define them as simply a result sigh polysaccharides are going to be just polymers of 1 or maybe 2 or 3 years some small number of subunits OK so like glucose strung together in a repeating the chain could give us cellular it's right we talked about that we talked about how would trade on cellular would 1 from cellulose which is formed from glucose so the polysaccharides of of glucose is called Celulose as 1 formerly of the talked about glycogen the other forms of depended on whether it's Alberta the beta Panama now today I want to get a little more complicated and talk about sequences of Isak rights of legal Sakharov's where it's not always the same carbohydrate the same hours Akright strung together and it turns out these have important consequences for the cell we're going to see that they can of worms at the totes for into bodies to react to that these conform on integers antibodies to react to it and they have other consequences as well so this reason we're going to talk about a legal satirized consisting of carbohydrate polygamists and more complicated things OK so let's get started I left off on this
final slide right here and I will showing you that up and put in link that glycosylation takes place in and applies in particularly and the gun and the gold he complex during the export of proteins after the synthesis of the riders a case is a very simple by Europe itself but I'm here and blue or they expelled proteins of the proteins that are going to appear on the surface of the cell and these get modified as the being transported by the goal G apparatus and this is so this is consolation is important for us proteins that are destined for export to the cell surface on but it's not found at all proteins that are found inside the cell a case of proteins that hang out inside the cell don't get modified it's only the proteins on outside of the cell so the cell is sort of this exterior of on lots of carbohydrates stuff and an interior that sugar this is sort of the gum drops the model for what a cell would look like right outside over here as all the carbohydrates and sugars and is chock full of proteins and DNA and RNA OK to right I'm OK so let's talk very briefly about how you assemble and in this case you be only at the power behind the like of proteins OK so an a leak like a protein has an oxygen that will be the recipient nucleophile for modification OK so in other words either a series or 3 in residue where this that this speed a hydroxyl and becomes modified by the carbohydrates so the High Flux also nucleophile the Electra file then must be the army sat right it's going to be adding to it and so the wager does this to convert carbohydrates into an effective electrify is to attach it to UDP OK so this is being attached to UDP and this UDP is basically a big leaving great we've seen this strategy before this is analogous to ATP where the AMP was just a big Leading Group for transfer of possible grip in this case we want to transfer this quite of United and so we attach it to UDP and then use an enzyme called ability because I was still transferees OK so that that is that this is a big leading room and so that in the end transfers silos to this hydroxide giving us a new and buy a new glycoside upon and then over here and in this case over here this UDP is attached to a different model sacked ride this 1 and city of Galacticos a down at and of it also can be used to modify the series or 380 insight shades OK so in and on these over here that our modified Burswood silos and turn into prettier quite counts so those are the proteins on the surface of the cell phone and better you know basically hanging out as big shrubbery the other ones the ones that get modified by the animosity of local galacticos these gallant acts they get turned into nuisance so these reasons are proteins that are secreted and are already sort of water-loving proteins that are important and that sort of the membrane interest issues between the unit so that air and water phases I'm being coy about this this this is the snot of the cell OK this is that the mucus nuisance nuclear strike the same route will take a look closer in a moment to see all of the stuff that gets them out on both of these so involved more glycosylation so in all cases the organist see today to start with a common core and then we're going to do a lot of modifications of so here is
1 example of this so after we start this common core that I've already shown here this is that the Galactic but this must be
silos that we saw in the previous slide there's a
series of Gladys Prince phrases that use UDP Galacticos and then transfer on 1 galacticos at a time so we start again of silos we add our wines 1 Gladys and Black a 2nd collectors in black and this gives us and we try Sakurai core that the political icon will use them as sort of it's starting unit OK so this becomes sort of the of the it's kind of like the spool that the threat is going to be 1 on too many different colors hysterectomy 1 on to the same school but in all cases were going to use a school that starts officers try sat right OK and so on this strategy here that I'm showing you can also be used for making repeating dies at satellites as well as director
let's take a look at some examples of this and you member on Thursday and I'm hoping your watch the Thursday videotape that's why did the quiz and if you watch the Thursday videotape of the 2nd last slide dealt with those new joint and of polysaccharides OK we talk .period the joint leaders sat rights and we talked a little bit about how these sort of things that were heavily sulfate is writes the sulfates were nice highly negatively charged the negative charge lacks water and also repels them from each other so that pushes them apart this makes a gel that so I'm pretty cushioning right because old molecules a kind of forced apart from each other and there's plenty of water in between OK so this is and the start over here so here's the protein that's going to be modified and Assyrian and as usual it always starts of those silos and then to Gladys Galgano Galvao and then there's a series of other modifications that are appended to this but these are things like that and ask children because collectors that also has a soul the grip of pay or animosity overlap those that doesn't have a R A a payout of sulfate group but it has it's still less interested he'll portion so in the end this case we can get on that we can get bursitis actually glucose and attitude glucose that it is you know attached so this gives us some heparin sulfate which plays important roles also understand the cell surfaces and herself signaling will see that later on and then over here these countries can contrite and sulfates Dermot insulates the user odd things Oregon East shuffled off into the interest issues between joints obtain notice that these a pretty heavily sold as well so he's a negatively charged gross topic meaning they tracked water OK so smart and
mucus if you need everyone's puzzled about what this stuff could possibly be I can finally tell you so these are highly glycosylation proteins that are held together by I sold by bonds and then and they have that the counter ions are calcium OK so when these things are synthesized the synthesizer these calcium ions him that has the effect of making them really Compaq when the super-size regular the positive charge on the calcium yet negative charges on the sulfates the whole thing ,comma across up really really tightly OK now what happens is when they get excreted the calcium ions are stripped off their grabbed by machinery and transport machinery that some exchanges them off so the calcium ions are pulled off and then what ends up happening is this stuff over here of all this negative charge then soaks up water like you know just in a tremendous degree to a tremendous degree so the water comes rushing and over here and that has the effect of tremendously expanding the volume of these nuisance so the super compact when they're in that the calcium neutralize state the calcium gets pulled away and now the spin hugely so this is how you little because you know membranes can secrete enormous quantities of stuff from such know small little cells and so on for example snails leave behind these tracks this is more or less the on elitists apparatus depicted here and I'm a very similar strategies used in disposable diapers which have these Polly acolytes peso again and have this negative charge that feeling unsatisfied and is looking for water and 1 of lines water grab onto a tremendous video grabs onto lots of water by weight and these are disposable diapers are actually kind of this miracle of of modern chemistry at these things as soak up enormous quantities of water relative to their weight against similarly that that's not in your nose is soaking up enormous quantities of water as well and are being secreted in that makes it very effective right as a way of forming up on a transition barrier between us and gas phase and then liquid phase OK I 1 year I got a fast by dieting student if you'd be a good idea for her to blow her nose more often as a way of a secreting carbohydrates and to lose weight and I thought that was really novel idea but the truth is that the quantity of carbohydrate and snot is actually very very low and because a lot of that stuff is just water because of the sulfates break this thing is so highly sulfate and that is really very little carbohydrate there it's mainly just water OK
so let's talk next about the and link like a that things are going to get more complex than complex here we've already seen how 1 0 OK so 1st of all there's 3 major types that are coming you carry out however they all have a common core this is comforting to us right this is similar to what we saw when we looked at people linked like copper glycoside sort of doling credit like icons on a previous life they all had that "quotation mark common silos in Galle Mac Oradell Almanac of course in this case we're seeing a very similar structure where we have the least 2 Glick Maxima arose visit glucose and Ezechiel glucose innings in a row so 1 2 and then disease Manasares over here and then things start to get a little crazy OK but you could see again this strategy here is start with a fairly common core not counting the Yukos but for the most part you know things are fairly common and then modify and customize depending upon the needs OK so everything is starting off pretty normal but then things start to get more wild as we go down here are OK 1 last thought I'd switch nomenclature earlier I was
showing you nomenclature like this from this starts to become increasingly less useful to us again in this case we have and then we have amenity that's appended to a glucose and its all faded and you know these things start to get increasingly baroque and so but rather than trying to depict the structures and spending time thinking about you is that of glucose is that a collector's instead we're going to transition to a much simpler or type of
nomenclature that's based upon 3 letters so glucose would be GLC
galacticos would be GAL and manners would be on etc. so from that from this these 3 letters she could kind of figure out what structures you look yet OK admittedly this would be a challenge for anyone in this classroom obtain I'm not asking you to do that because I'm not asking you to memorize the mine structures of momma Sack writes that are found in the struck and these founded in humans OK but I just wanted to be comfortable with the idea that these are carbohydrates news does carbohydrates you never know when this information is going to be useful and who knows maybe some pharmacology classic to take many years from now OK let's talk a little bit about the mechanism work like Castle transfer it turns out this is actually not a very straightforward mechanism I did well and this in the case of the old linked like asides and because of those those to works so well oxygen is a fantastic nucleophile oxygen doesn't have a carbonyl nearby but for the and linked like asides for that things are a little bit more are complicated and that's because we're going to attach things not to nitrogen found unlicensed side chains but instead nitrogen that's bound and largely on asparagine side chains and so the nitrogen over here is next to a Carbondale it's a carboxyl right this combat and functionality is not nearly as nucleophilic as just a free-floating nitrogen with its here hanging out member earlier in the class I told you that the lone parents nitrogen spends a good 40 per cent of its time hanging out as the resident structure forming a nitrogen carbon double bond rate here and because that nitrogen carbon double bond is their 40 per cent of the time the lone pair on the nitrogen isn't so reactive it doesn't have some moral imperative that makes it wanted ran out the door in the morning and start looking around for electrify it's extremely on reactive and so instead and what happens is there a specific sequences that presented asparagine in a way that allows this reaction to take place OK so this is an example of substrate assisting catalysis I'll explain in a moment but note in the structure of the use of these like a seal transfer raises fears of base the base candy-coated at nitrogen and electrons that are then bounced away to form the next carbon double 1 but then on and near Phi hydroxyl bearing side-chain either a searing 3 fears of a proton beckoned Prodi make this Carbondale and so the net result is an immediate taught Amir this structure here which has an unmasked loan here otherwise the lone pair is hidden away it's not so available really for doing reactivity blood after this this need sort the side chain of gets into place and gives you the perfect Proton nearby and then all of a sudden the lone pair is uncovered and ready for reactivity OK and safe doesn't have anywhere to go it's like naked out there and it's trying to figure out what to do next and so it will more readily attack on this activated like him note that X over here is some leading grew so already saw earlier today 1 good leaving group was UDP and we don't have to dwell on the structurally grip but suffice it to say something that likes to take off OK it's effective leaving grip note to the structural work requirements for this reaction to take place there has to be this band this 180 degree turn that pleases the hydroxide in close proximity to the carbon of this asparagine if you don't get that bend the structure of the reaction doesn't take place that's absolutely mandatory for this to To this reaction OK so am I call this an example of substrate assisting catalysis because this is catalysis that assisted by the substrate itself the substrate the starting pitcher for reaction is this asparagine bearing no tea and that participates and in this case by providing acid Louis sorry Bronstad acid catalysis the protein this carbon heel so again on certain sequences are required hours not correct here it was Syria over and threonine is not available at this position it's game over a case of this only works with certain substrates again actually gives you a degree of selectively brace yourself
now things are getting a really complicated what happens if there is a very complicated structures get synthesized bears and linked to like hands and then they get trend backed by sisters like a like a site like Hossa bases the class of enzymes that we saw last Thursday so what happens is you get these theory complicated structures coming out and then the kind of randomly chopped apart by a series of different in this case on glucose and glucose today's as warm and cities as these are just simply glycosylation is these are enzymes that cleave apart but quite acidic bonds and we saw a good example of that last time we talked about like designed I think that she's seen up for a couple of weeks running so here's the thing now because these glucose today says and these quite possibly says the general on programs to be really specific about this bond versus this bond and this has the effect of introducing randomness onto the surface of yourselves so really the whole 2 men like him and that gets appended appears out on the surface of the cells and is sort of a little bit random it's not exactly program that this element of random last dramatically increases the structural diversity of the chemical compounds found on the surface yourselves and note too that this diversity is not encoded by the Chino OK this is diversity that's kind of this is post-translational modification diversity that just adds like a whole new element of complexity to thinking about the chemical environment of the cell and I'll be honest this is daunting OK this kind of stuff of randomness and you different structures scares the heck out of I don't know how to even think about this sort of thing it is very very intimidating in a way the idea that I cannot determine exactly what the structures on the surface of the cell and furthermore that the analytical tools that have available to me as a chemist in 2013 are not good enough for me to go in and tell you exactly what the structures on the surface itself I find that I'm really annoying and I'm very very intimidating OK and so this is a very important frontier and chemical biology and I encourage you to think about it I think he wanted develop the plus proposal topics come up with a way of figuring out what the structures on the surface of the cell I guarantee you that will rocked the world of head because and we know that these are important in various diseases yet we don't have a good way of characterizing what they are it's 1 of the last frontiers analytical chemistry really
OK and I'm let's talk about what they did right so 1 thing that was sorta early on is maybe they're hanging out on the surface of the cell and to grab on to passing other cells and a great example this would be a T cell communicating with an antigen presenting sell down here and we definitely see the carbohydrates there highlighted in these sort of brown structures that hanging out and you could see the union of making contact and they're doing stuff but the truth is what we cut them off the surface of the cell or we set up a cell line that doesn't produce those the cells talk to each other just fine here so it doesn't seem to be required for every communication it always seems to be required for some communications some molecular recognition between cells 0 and work all that we discussed earlier have communication between cells and communication between proteins is like Abril process where the proteins in the molecules view each other and look for complementary services complementary functionalities indifference but structures that's the sort of thing that we're talking about here so in this case we can remove the carbohydrates and the 2 protein that 2 cells talk to each other just fine OK
but here's 1 thing that they do seem to do so for example they can play a key role in in body recognition so far the like asides that modify and bodies tend to be pretty had genius again that's the whole randomness that we discussed earlier on the other hand the do seem to be required for and a body functions OK so here's a legal staff rides down here and here's the structure in body they introduced you wade back I think on weak 1 of this class and then recall that they're going to be recognizing antigens up here and there modified as in legal icons and again as and link like him as they have a common core that we discussed earlier today and then there's a bunch of silent acids and other types of modifications that are appended to this and even know they're quite had a genius the seem to be important if you produce a analyze about the carbohydrates they tend not to fold well they tend not to pump function as well that recognition so the carbohydrates seemed to play important roles in protein folding chair that's 1 role on the virtue they seem to play important roles in soluble icing proteins and number 3 there also seemed to arm the important for protecting structures that otherwise might be recognized by the immune response they simply do a kind of providing shielding like the armed forces feel there's something that keeps that immune molecules a big
challenge for us the challenge for the biotechnology industry in general is that of the proteins that we produce are being produced largely by human cells OK and so on but in the biotechnology industry we sold something like 25 to 30 billion dollars billion with B worth of everybody's last year so this structure here that's a
25 billion dollar plus industry in United States paintings are used for everything from treating cancer to treating autoimmune diseases but on
in about week we we rely very heavily on Chinese hamster Overy cells to produce the the into bodies for us In an thinking why Chinese hamster race and why cells from that particular organism it had it's merely historical these ourselves 2nd row really robustly they really without a huge quantity of antibodies and I did contribute can grow the cells in 10 thousand leader from mentors can mean that the size of this the scale of this production boggles the mind they just imagine this whole room here that we're in the field with fetal calf serum which is what these guys like to eat you know or something else it's kind of like this year and found that a bloodied of artificial Justice whole room filled with this stuff and sells sloshing around and annual budget chemical engineers that carefully controlling the oxygen content of the carbon dioxide content and the pH of the solution and the level of control was pretty amazing to but all that is necessary to produce this 25 billion dollar products and here's an issue that comes up when we look carefully at the identity of the carbohydrates found on the surface of the bodies there's divergence between what's found on human antibodies shown in this column versus what's found in these Chinese hamster ovary cells found in this column that diversity that doesn't see divergence that doesn't seem to have very much functional consequence we seem to be OK with that so antibodies that are produced in this way are given to patients on a daily basis and then seemed to be perfectly functional OK over a long long terms OK
now along the lines of giving stuff the patients and modification Michael icons is a very important side reaction that takes place almost as soon as pharmaceuticals are are taken by the patient and this is 1 that I know someone in this class is going to end up spending a lifetime studies vary when it goes into pharmaceuticals you know some small percentage of you will be concerned about what happens to the pharmaceutical after it gets taken up by the patient and 1 of the 1st reactions that takes place in the body is the body tries to solubilized effect oftentimes pharmaceuticals are pretty insoluble and merely talked earlier this quarter about cytochrome P 4 50 that has a strategy of introducing oxygen to solubilized sapiens of hirings things that otherwise would be insoluble in this case that the strategy for soluble isation is to transfer this who could miss glucose this wanted I'd molecule to it so starting with UDP who carotid you can basically transfer this to give us a glue carotid with carotid dated molecules so there's a hydroxyl in the and in this the compound that's being given to the patient that then gets becomes the nuclear file to attack this activated go like him to give us and they modified product over here and this thing is going to be a lot more soluble has negative charge there's lots of hydroxyl 2nd form hydrogen bonds with water and so this takes this has the effect of taking something it's pretty insoluble and converting into something is really soluble again this is a good strategy this works a lot this is 1 of the very 1st breakdown products better found when we look at what happens the pharmaceuticals after their ingested by patients OK last topic that I want to talk to you about and who had glucose with the serial was morning 3rd who like sugary cereals for breakfast OK I did too I want sugar in the morning it's OK so chances are that that glucose that this city prosecutor has now been broken down into glucose and fructose and that stuff is now running around your bloodstream as we speak and in response to this year bodies of all this really effective way of coaxing out this glucose to be the taken up or taken down and probably even know about this this is a system that's controlled by the hormone insulin a case of way this works is that the goal is to have a state concentration of glucose out here and there in the blood vessels and Lucas is constantly being either expelled or 1 for pumped in insulin triggers glucose uptake by itself so after the insolence released glucose gets taken up by by the muscle and fat cells and they do with it what they will depend so I'm when you're sweating when we took the little quiz earlier that was your glucose going to work k the
problem that no fears on when the cells become but less sensitive to insulin and this part over here shuts down when that shuts down the concentration of glucose in the blood vessels skyrockets and the problem is this glucose stuff is not totally benign OK recall earlier we discussed how to reform the heavy acid California Annika form the hired for the AL the form is a very effective electrified and if you have a high enough concentrations of lots lots the forms running around looking for some nucleophile to react to it and that can't be good OK and so what happens is
you end up with the random modifications of proteins on the surface of the cell to this happened spontaneously to all proteins found in ceremony in the the blood on and this causes problems OK so here's the structure of a protein that's been heavily like oscillated and on these modifications our own spontaneous season nonenzymatic we controlled and they just happen and not spontaneously let me show you the mechanism for that about for this reaction OK so
here's glucose over here here's lysine on some service self this is called serum albumin a case of human serum albumin is present and Millie molar concentration in your blood and there will be a lysine side chain effect and then reacts with the UN electric bill at the end of mirror carbon of this glucose OK this is a reaction called the Commodores reaction in case that happens pretty spontaneously from key intermediate here we don't think it can mean anything that is a somber during reaction go yeah yeah surgeon at the time OK 7 nucleophile what's electrified come the on but the call at the With the yes the rise in the glove this job OK so this is an American urban can two-time rise into an allied back and then react with this this and the need to give you a shift basis and I through some other you know proton transfer steps you get to this product here OK this doesn't look so bad right the problem that it is on this sets you up there for something that is a lot less than I'm OK we have a Carbondale over here that's a new electrical site and this can arranged to give us an Alpha unsaturated video another lysine either on the same protein or neighboring protein can then react with this and the net effect here is to cross to proteins a case you take these 2 free-floating proteins that are normally just kind of swimming around and happy as can be a near us here and now you tendering them together or even worse you can bring to the surface of the cell so undersell doesn't know what to do about this the new system doesn't know what to do about this and system really is kind of a sledgehammer it responds the way it likes to respond which is to increase information and so the net effect of this is you get on a massive you get information response which 1 you know kind of spirals out of control OK so you get these things the tethering carbohydrates and services cell and then they get more more complicated and more more baroque as more reactions take place and you just start to accumulate these advanced glycosylation and products that are you know we lead to inflammation and disease OK so this is why I can't do much glucose is a really bad thing and on our American diets are seen to be ideally suited for maximizing concentrations of glucose which is a really particularly that think the pernicious thing really it's so advanced by consolation and products lead to inflammation it's kind of like accretion rate it's it's sort of getting in In the way of the of the immune system
OK so naturally being chemists and being innovative people we like to that stuff that would offer us that see wonderful taste of sugar sweet but not offer the same glucose and potentialities so we've been doing things for years that involved trying to I have the same amount of sweetness but just lower concentrations of glucose syrup example worked as it is like to X Sweden's to but but because it's just half of the sucrose it's actually on half the calories and it doesn't have a clue because that can be floating around looking for reactions to do OK so I can get protest pretty readily out of honey honey is twice this week for the calories and it doesn't taste the same I know but it's pretty effective and this is another 1 trillion US was also used for extensively so we do things like this all the time will will serve to 1 thing for another something's a sweeter than others and offering less calories this is done for you know 100 years or so maybe even
longer OK the other thing that happens is we also invented a series of compounds that don't look anything like carbohydrates but activate the same carbohydrate and arrests are back the same receptors for sweet taste so for example Astra came as the army died peptide that's methylated at the C-terminal that on his 180 times sweeter than sugar pay you can eat this stuff and it is insanely insanely sweet but immediately issued your lips going like that for hours and it's really really that sweet potato like stick your tongue in this affair but that is the the problem with this is that it can and it has a rearrangement that warranted Ikea papers saying that this is the director of the Brazilian and on near Tame it's more modern variant of wasted that IQ papers 18 by having this figure and you know functional group on the side and it's also way we sweeter sucralose OK suppresses kind of gold standard here as table sugar 10 thousand times sweeter for the way it as kind of amazing the and the
other thing is we've also come up with things that look like carbohydrates but cannot be on a high July's and digested so for example the squaring substituted versions of sucrose OK so this is like grows over here except now instead of hydroxyl so we have chlorine this is a compound called sucralose and you could also I so that you can also isolated from plants from the sweetly plant shown here you can isolate steadier on to me Fuentes a little bit better than out of any Windows steadier with the coffee but I can deftly cases talent it just doesn't taste the same 1 that gets even wilder than that there is no amazingly sweet compounds that you can extract out of the bushes and plants that are so sweet that they can overwhelm your sweet receptors and the EU With this permanent sweet taste that affects the flavor of everything you eat afterward a case and you can eat these compounds on 1 of them is called like the miracle barriers something like that and you eat this stuff and then you know for 10 afterward you can eat like lemon juice and I Nutri Clement use for what he calls and stuff like that and everything days we need is a really good sweet and observational we're kind of stuff is just amazingly fast OK on any questions about carbohydrates yes No you just yet but a yeah taking
up a position that is OK yeah that is an issue because this type he looked no longer taste sweet again the problem is when you cook with ascertained that the high temperatures encourages us before OK and that's a problem because of you want Swede over here and so we have something it's not sweet and so that's why we find aspartate came in I like Coca-Cola like Diet Coke and erections and what's actually and I hope that you find it in my diet soft drinks but you don't really find it in say diet doughnuts OK write anything that encounters high temperature on African is not going to work for so instead and we tend to
turn to things like syphilis and other things the trustee over here I have not tried it have you OK and like to try it and really trying things that is where the you know fully edible and OK but let's move on I
want to talk to you next about polypeptides tights and earlier in the class and I told you that to organize everything quintessential problem of modern biology were down down here we talked about a sack rides were now at the point they're going to talk about Polly tides and intervenes in the next couple of days and this is fascinating classes of compounds that really gets under played in biology classes but really deserves the spotlight because they do so much for us these
are found on "quotation mark we talked about the structure and 3 where there found the found in all kinds of antibiotics and that's so for for example this polypeptide tide is a very nice fatty acid and on all public key tides and terpenes art form from repeating subunits which I highlighted here so in black these 2 carbon unit subunits are going to be introduced in modular fashion such that the red bonds can be synthesized the same way every time similarly terpenes are modules of 1 of the 5 carbon units by Supreme units better strung together and connected by these red bonds OK so we're going to be talking about the focus again he's a composer repeating subunits of modular bonds
OK so here's some examples of Polly key tights and I think this illustrates the tremendous structural diversity and of dairy the beauty of molecules UT these are beautiful but because look at you as a referral light over here is just so you to me it has a lack structure lots lots of functionality sticking off of it and it's got a key town over here and there and it's perfectly evolved to the point with a very effective antibiotics to this is that there were 3 Ritter mice and in and out of that many if you've probably encountered at some point in your life times and I think it means are also extend to the the UN fatty acid and on that's as well so you can get really complicated apology tides like this 1 you can also have the aromatic compounds these aromatic compounds are basically folded up and the fatty acid type things that have a key step of carbon-carbon double bonds that then cycle lies to give you these aromatic rings so if you wonder when we talked about how less aromatic rings for their being formed along the same Polly he tights and faces this early in the quarter quarter I suggest you don and Rebecca Meissen a variant of the compound shown here and that was synthesized by Polly the tides and faces a case synthesizers By cells so but OK so on all
polypeptides he are built by a straightforward algal reaction but because this Algol involves an ester it's called by the name cleans it's Eccleston reaction OK this is why I love that although reaction this is how the majority of carbon-carbon bonds are formed in nature that the vast majority are performed using this reaction and so I want to take a moment just to appreciate how this works OK we're going to start with the unburied that's found in the laboratory OK so in the lavatory and although reaction on you which stars Clayson and reaction you start with an and then you add some sort of strong base that would then deep-red this alpha proton over here give you an evil late in the in the late can attack electron swish down here switch over here and they kicked all the way up to the oxygen the net effect is we have a new carbon-carbon bond fake here in this works really well this is a great way to vacant carbon-carbon bonds they literally have experts bills carbon-carbon bonds and so and then in the end this Tagesspiegel intermediate collapses and that gives us this new compound that has a new carbon-carbon bond on it the problem for danger is that nature doesn't have access to strong bases like this 1 that strong base is totally unique just to this particular but you know what's found in nature OK case so doesn't work so well for and the 4 cells OK just don't have access to bases that army strong enough to readily deeper protein an alpha proton and so
instead of what nature tends to do it I'm a little trick that I'll show you a couple slides from now because so forcefully just set the stage and what we're going to see it is required to see instead of esters we're going to see file esters but it's also called equation as well OK we're going to see buyer Leicester's between the the acid Hilco areas like this guy Her probing Neil so if the compound needs an extra metal grip you start with the shelf that has the preppy e-mail if you just want to carbons penny stock of the acid he'll OK but the idea is the same we get more or less the same reaction and the problem is these to and 3 current building blocks are small and slippery it would be very hard for the Celtic like the Rob onto these things if there were just 2 or 3 comments so instead the strategy that the cell applies is that patch of big old handle to the 2 in 3 carbon building block and that handle is this molecule down here called coincide so from now on we're going leave bought this part we're going to simplify it as just coed cannot all this over here that's the gamble because the enzyme grabs onto this part and those down here that's a 2 or 3 common part down there that makes sense OK let's get back to a strategy that the cell users now To do it squeezes again I've already told you the cell doesn't have a strong enough space to make big plays that we use in the lab work so
instead with the cell does is at the carboxyl Leyshon reactions OK where it actually does the and Alexi issued incorrect it's it's going to do this the carboxyl Asian loss of carbon-dioxide to give us an intellect take structure here is missing a carboxyl will have OK so again the strategy allows it to access this in a way that without having a really strong base of Arab billable time and in practice things get even more complicated in practice the enzyme that capitalizes the glazing condensation on simultaneously provided the recipient of a Esther viruses at the same time that it holds in place this year or in a light OK and this reaction works for both to carbon as shown here for 3 carbon subunits released to methyl groups just become like most spectators Syria chemistry of course Camino tightly-controlled inactive site OK with that so me we've been on the places just invoke the clays and from now on as their it's understood OK so we don't have to be mechanism plays in anymore 1 but here's a mechanism that we do have to talk about it 1 more that's also kind of going to be toolkit and we'll see quite a bit and it turns out the cease-fire Westerners can very readily do rapid exchange city can go from an SS deal escalate by Leicester to say the entire Western on simply by nucleophilic violate attacking the carbon taking up for me attach Riegel intermediate which then collapses to give us now this as a Chilean is attached to the violator of the Sistine side chain this happens really readily obtained this is going to be important because earlier I said that we have these 2 carbon things attaches big 8 candle but eventually were gonna want stuff that sort of in exactly the right spot at the right time and this gives away for the enzymes have assisting interactive side and then grab onto a to common piece very specifically OK so what we're going to see in a moment is 1 piece of the reaction is going to still have desk away and the other piece will have to be attached covalently to the enzymes active site I sounded simple reaction nothing too special
OK now from those simple reactions that I showed you on the previous slide all kinds of video chemical craziness can emerge for example you could very readily form all of these fatty acids a case of these fatty acids all and you know carbon unit to Communists have built up on these can basically be synthesized using exactly the same place a reaction that I should a previous life OK this is kind of wild and before I get too far I want to introduce you to some nomenclature 1st the real aficionados memorize structures don't memorize the structures of these OK instead
what I want you to know it on this Omega nomenclature case of Iomega nomenclature counts from the last comment of the fatty acid tale over here on this side this is the carboxyl 8 you can number these columns 1 2 3 4 5 but it turns out actually the key to controlling the year on structure and their and their properties is the carbon-carbon double bonds from the tail Of the fatty acid In OK you probably have heard omega-3 fatty acids and being important in your diet omega-3 fatty acids refers to having won 8 carbon-carbon double bonds that's 3 comments from the tail OK so this 1 would be an American 3 6 9 fatty-acid figures that positions 3 6 and 9 counted from the tail and you have a carbon-carbon double 1 that carbon-carbon double bonds crucially sets a lot of the properties of these and fatty acids 1st of all I noticed that all of these carbon-carbon double bonds are assessed carbon-carbon double bonds and other words they have the help heal grooves on the same side check this out all the ones on the
previous slide also stressed the vast majority of carbon-carbon double bonds founded that's found in nature are assessed all of them OK not Transall offense trans fats are found in artificial fat sources that have been partially hydrogenated those trans fats are difficult to digest and I tend to do things like libraries and things like that which is why the associated with heart disease OK so naturally
occurring accessible offends counted from the Omega side over here and fish and can all our ills have a very high concentration of these omega-3 fatty acids and is crucial to maintain the correct this past year cells have a certain ratio Of these omega-3 fatty acids verses omega-6 fatty acids so omega-6 fatty acids found in things like corn oil and sort of sheep soybean oils you note that inexpensive reports sought forms well-liked safflower oil and you have things like that that are found in processed foods the problem there is that when you're the ratios of omega-6 to omega-3 and get off from where they should be ideally the viscosity of your cell walls of early but your plasma membrane not the walls but the membrane changes and that beats viscosity seems to be a crucial characteristic of the brain function and other functions and so it's really important that in your diet you have enough omega-3 fatty acids again this is omega-3 fatty acids to replace these omega-6 fatty acids it's simply an equilibrium depending on your diet omega-6 you the more omega-6 is that appear on the surface yourselves OK
hiring these things this is the machine of dreams this bill machine over here synthesizers these bats and in a truly wondrous cycle OK and I absolutely love this chemistry because it's totally understand that it's so incredibly powerful OK so what we're looking at here is a schematic diagram for fatty acids and it's a case of this is the thing that's going to be
synthesizing molecule like that and it turns out that the
enzyme is guilty of 1 chain replaced so it has a single continuous and avid bond of linked protein there happens to be a very large protein this thing is is a monster in terms of size and on different domains of the protein are pulled up into different enzyme active sites and each 1 of these enzyme active sites is labeled with a little codes that all the Cypher for you next OK so we're going to have in the very center for example a domain called the sole carrier protein this is going to act as a robot arm that's going to be carrying the intermediates between each of these active sites and the whole thing is going to go around a bunch of times as its acted upon during the synthesis of the facts take around so I think great let's get started with that 1 this is the loading of the starting material onto this carrier protein carrier protein looks like there happens to be a Syrian residue and over here and that's going to be and where this thing is going to get loaded onto OK between this series between b and they're starting at the starting peace over here there's also this fast so upended by you group that just gives it a little bit more space a cake stands at a little bit further a case of a secure protein is over here and again we have a file over here the file is perfect for the file exchange of fire exchange that I showed on a previous life OK file bank in each student exchange with as a single Coen to set you up to start this process
OK so here's how it works here is that while on the possible Penn also possible Panther
final group over here
here's the violate it attacks the Segal Co and you get in a streams insulation reactions OK so you could be the start off with 2 gardens or you can start up with 3 Carver's 3 Commons is nice right because that sets you up performing in the late so it kind of depends on if you want to start off by being Lake being nucleophile or start up as being the other electrified fence
erected so that the next step is a carrier protein on the robot arm the past append to Pinal means news there Seal Co at that site moves this single grip over to the Quito's days active-site abbreviated chaos chaos then does a bio Esther exchange grabbing onto the Seidel of functionality and setting you up for a clean isn't condensation here's firstly D carboxyl Asian too warm the INA late and then here's our plays and reaction that we've seen previously that gives us the new carbon-carbon bond rate here and in the air and basal carrier protein comes back and then picks up this product again OK so basically they poaching delivers a to 1 of these active sites the reaction takes place in this case equation and then at Pixar backed up and moves to the next site and that's really elegant stuff OK the next reaction that can take place is the key to a reductive noticed
that the product over here it is a key town and so on you can obviously Keaton's don't appear in an these fatty acids and so that we have to get rid of the key town so the 1st step is to do a reduction of the the town's nature's
hydrates choice is pH this is analogous any DH that we saw earlier in the quarter and hydride gets kicked out reduces the on the carbon deal and that gives us an alcohol this alcohol then
could be eliminated by a dehydrated a case of the high case predates the hydroxide and that we do it as a straightforward either each EU elimination already 1 CBE the jury is still a little bit mixed on this 1 and in the end there we get a carbon-carbon double bonds and then this carbon-carbon double bonds can be reduced using gas and energy pH nature's reductive using exactly the same reaction were less OK and
in the air and then then the very last reaction nobody simply hired to icing off from diesel carrier protein using an mechanism that's analogous to a searing gradients OK so let's put all this together
OK so here we are this is our 1st schematic diagram it's carrier protein starts off 1st and it gets loaded up and then it brings the casino group to the Quito states went to bring the Citigroup to the Quito days this then does it squeeze in reaction to it comes over here to the Quito without days and then the Eno and then they dehydrate haze over here and then Uniroyal reductive I know these things don't seem like they're in order a kibbutz schematic diagram it seems like it's kind of jerking back and forth but 1 that's more or less what's happening and then when you get to after the 1st 2 carbons are added and then you get back to the Quito said there is an United 2 carbons with her 3 carbons get to this go to this 1 go this 1 go that 1 and repeat the process multiple times until the fatty acid can no longer fit in the fatty acids and days at which point then this fire West race comes along and high July as is often the fire Leicester from the carrier protein OK when the
stock was stuck here when we come back we'll be looking at even more complex colicky ties and other synthesis


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