in this biochemistry video we will be talking about purine synthesis sometimes referred to as denovo purine synthesis let's start with a brief overview just so you can familiarize yourself with the content that I'll be talking about so purines are substances that are incorporated into DNA RNA ATP GTP cyclic cgmp and co-enzymes or in other words they're very important and because they're very important the body needs a way to create them defects in purine regulation can cause different pathology like cancer gal neuropathology and immunological diseases purine synthesis as it's aply named creates purine nucleotides from a starter molecule so the body has various ways to grab different substances and then strap on more pieces of chemical information to those substances and create pure Pine nucleotides now the goal the overall goal of denovo purine synthesis is to create something called inosine 5 monophosphate otherwise known as imp now imp is an intermediate that can be transformed into either or GMP depending on cellular needs and as you'll see depending on whether you create or GMP those individual subst es will go on to selectively create the nucleotides that you want lastly purine synthesis is an energy intensive pathway so it requires active transport of other substrates and co-actors from other biochemical reactions so whether we're talking about other biochemical reactions the products of those reactions are going to get shuttled via active transport there's going to be a lot of energy input to utilize them in the denovo purine synthesis p pathway so with denovo purine synthesis where we start is with ribos 5 phosphate and as you may recall from my other video on biochemistry this comes from the pentos phosphate pathway so we start with ribos 5 phosphate and ribos 5 phosphate is converted into something called five phosphor rosil one pyrophosphate or simply put on USMLE comlex and usually in class exams PRP p p so we convert ribos 5 phosphate to PPP and the enzyme that catalyzes that conversion is PPP synthetase now as I've pointed out in my previous biochemical videos anytime you see synthetase it's going to make whatever the name is in front of synthetase so in this case prpp synthetase is going to synthetase or synthesize or create prpp so that helps you remember what actually is happening here and as you can see this step requires a ATP so ATP in the process will go to now that we have prpp PPP will be converted to five phosphoribosyl amine or 5 p and the enzyme that catalyzes this conversion is glutamine fosil ribocil amot transferase or gpat this is the rate limiting enzyme of denovo perion synthesis so it's one that you absolutely need to memorize for whatever reason on exams on USMLE on comlex test right ERS love to ask you the rate limiting enzyme of various reactions so here's something you should know and please note that in this step glutamine is converted to glutamate so one of the things that I'm going to point out here is that denovo purine synthesis requires substances one of which is glutamine and there's there are more coming but glutamine is just the first that we can see here now once we have five phosphoribosyl amine or 5 P that will undergo a series of subsequent steps which I'm not going to show you because you don't need to know those enzymes and you don't need to know those byproducts but it will eventually create imp so we go from 5 P down to imp through a series of reactions that you really don't need to know however what you do need to know are the intermediates and the co-actors that are required in each of those steps because this does show up on tests so from 5pr down to imp you will need various substances including glycine formal tetr hydrolate glutamine carbon dioxide and aspartate and then as you saw the one step above we needed glutamine and ATP so you need to memorize these five substances they get you from 5 PR down to imp because the whole purpose and a lot of the your in-class exam questions will be about what kind of native substances are going to be required to derive nucleotides and here you see the answer so glycine formal thf glutamine CO2 and aspartate and so the way that I memorize this is go forward and go create an imp G for glycine f for formal tetrahydrofolate G for glutamine C for C2 and a for aspartate so in this step going from 5 P down to imp you go forward and go create an imp and these things are very very important for denovo purine synthe is so now let's say we've gotten down to imp imp can be converted into either or GMP and then depending on which one you create will create addon nucleotides and GMP will be used to create guanine nucleotides so in other words imp is the very important Branch point in denovo purine synthesis that allows the body to select for which nucleotide it wants to synthesize now something I want to point out here that's important is imp being converted to GMP that is done by the enzyme inosine monophosphate dehydrogenase and we'll come back to this in just a second but there is a there are various medications that inhibit this enzyme so just keep that in the back of your mind so now if we go back to our overall biochemical pathway here's what we have ribos 5 phosphate turns into P PP and then p RPP turns into 5 p through the rate limiting enzyme gpat 5 P will go through the series of five or so reactions that will bring you down to imp using those various substances that I gave you that pneumonic for and that will create imp and at this point the body will decide if it wants adenine nucleotides or guanine so it'll either turn that IM into or GMP now some feedback mechanisms you should be aware of is that once the body has created or GMP these substances will partially or fully inhibit the rate limiting enzyme of denovo purine synthesis so if you have GMP present by itself it will partially inhibit GPA if you have present by itself it will partially inhibit gpat and if you have both and GMP together present it will fully inhibit the rate limiting enzyme gpat so in other words the downstream products from denovo purine synthesis will turn off the rate limiting enzyme and this should make perfect sense to you because if you've already created the goal product of your pathway you don't want the pathway to keep going so once you get to and GMP it turns off denovo Pion synthesis by inhibiting glutamine phosphor rosil Amo transferase and that's what I'm trying to illustrate here now we have certain medic medications this is more relevant for USM or complex we have certain medications that are going to inhibit various points in this pathway and these medications come into play as immunosuppressive agents that can be used clinically so the first example is Asa thoene and six mercaptopurine both of these medications inhibit denovo purine synthesis overall so you don't have to worry about an individual enzyme or anything like that but know that six m captop purine and aprene which is six mercaptopurine prod drug both of those inhibit denovo purine synthesis and then lastly we have two more medications one is called mof phenolate and the other is reirin and these medications are going to inhibit inosine monophosphate dehydrogenase which is the enzyme that I showed you one or two slides back that converts in into GMP P so we have these various immunosuppressive agents that can selectively Target and inhibit different points in the denovo purine synthesis pathway now that does it for this video but this video is going to be part one of three so the next video that will be posted will be perimidine base production and the one after that will be about puring Salvage deficiency so keep your eye open for those two videos