hey everyone in today's lesson talk to guys about the primitive synthesis in metabolism pathway more specifically and talk to you guys about why we need primitives what permanence are why primitives are important in human health I'm also going to tell you guys about some drugs that are used to actually inhibit protein synthesis during disease states such as cancer so it begin what our primitives well primitives are six-membered nitrogenous bases so we've got one which is known as cytosine another known as uracil and another known as thymine now an easy way to remember this is the kind of the mnemonic device known as cut the pyramids so pair pyramids should help you remember pyramidal and cut so Cu T for cytosine uracil and thymine now these primitives are very important in RNA DNA synthesis in uracil is the equivalent of or the analog of thymine in RNA now permian synthesis requires a number of things one it requires glutamine another he requires aspartate and it also requires tetrahydrofolate which is a derivative of folic acid or otherwise known as vitamin b9 so as you can see here this is one of the main reasons why we need adequate levels of vitamin b9 in our diet so to start off the cell utilizes glutamine to ATP and co2 and combines all of them together and process them all together by the enzyme carbamoyl phosphate synthase - now you may remember carbamoyl phosphate synthase one or cps one in my urea cycle video and this is the cps - is actually the cytosolic version of cps one and they do very similar things and the thing they do is they produce carbon one phosphate now in the process in this process glutamine is actually converted into glutamate now you might not have heard of cps - but you may have heard of cad now I mentioned CAD in my mTOR signaling video and i mentioned that p 76k actually activates cad now and I mentioned that CAD is important in permitting synthesis and that's what we're talking about here so this is the actual protein that's very important in in permitting synthesis that's regulated through mTOR now this protein or in this enzyme or enzymatic reaction is also the first committed step in permitting synthesis now this enzyme is actually regulated by inhibition through a UTP and is actually activated by ATP and PRP P and as you remember P R P P is that all-important molecule that I mentioned that's produced in the pentose phosphate pathway now once you've got carbamoyl phosphate what happens is it gets converted to carbon well aspartate by the enzyme aspartate transcarbamoylase and it actually adds aspartate to the carbamoyl phosphate and to Peru's carbon well aspartate once you get the carbonyl aspartate it goes through a couple of steps including through an enzymatic reaction utilizing dihydrate orotate dehydrogenase to produce erotic acid now this is the first primitive nitrogenous base that's produced now this is not used in DNA synthesis but is it is actually commonly referred to as the first nitrogenous base now this enzyme is important I wanted to mention dye hydro or tait dehydrogenase because it is actually a target of some drugs that actually are used in rheumatoid arthritis and one of them is left food Noam ID and that's actually inhibits this enzyme now once we've got erotic acid what happens is the cell needs something else and now what it does is it actually needs PRPP and what how it does that is it goes through again through the pentose phosphate pathway it produces ribose 5-phosphate and through the enzyme PRPP synthase it produces five five zero one pyrophosphate or PRPP and PRPP synthase is actually inhibited by ATP and gdp and is activated by inorganic phosphate now one you have PRPP neurotic and so they actually combine to form or auda beam 5 prime mono phosphate or onp so OMP is the kind of the product of the two erotic acid and prpp being combined together now once you have onp what happens is it actually gets converted to UMP by the enzyme ONP decarboxylase now this enzyme is also inhibited by UMP and cmp so it's kind of a negative feedback regulation on this enzyme then UMP is converted it to a UDP and then UDP is actually converted to deoxy UDP or D u DP by ribonucleotide reductase and UDP can get converted to D u n p1 which can then can get converted to D T n P now this is the critical step that I guys I want you guys to remember Phi middle eight synthase is the enzyme that converts D u NP to dtmp so this is the all critical step here because this is where a lot of regulation and a lot of our drugs in medicine are actually used to target this particular enzyme so thigh mid-late synthase guys remember that five middle eight synthase now this enzyme actually requires n 5 and 10 methylene tetrahydrofolate and I know that's a long name but really all I want you guys to remember is that it requires tetrahydrofolate or it requires vitamin b9 so this enzyme requires folic acid or vitamin b9 now this methylene tetrahydrofolate is actually produced by an enzyme known as dihydrofolate reductase now I'll talk to you guys about this in another video but the main point I want you guys to know from this is that we have very important drugs such as methotrexate in 'man operon that actually inhibit dihydrofolate reductase now methotrexate is an important drug using as a chemotherapy during for various types of cancer it's also used for or for abortions as well and this is where it's actually targeting so method tech methotrexate is an inhibitor of diet a hydrophobic reductase so it's pretty much inhibiting folic acid utilization so by mid-late synthase cannot operate now there's also another chemotherapy drug that actually acts directly on thigh middle-aged synthase and that is five-floor year or so and again this is as I'm a treat for it's a chemotherapy drug that is used in various types of cancer but the target of five Florrie or so is actually that minute late synthase so once we have dtmp it'll be converted to deep dtdp and then to D TTP now going all the way back to the near the beginning of the pathway UDP can actually be converted in a different side reaction to UTP so it can be converted to you to be instead of e d UDP now remember guys the D stands for deoxys such as deoxyribonucleic acid or DNA so instead of DNA it can also it can be actually produced into RNA so that's why this is the side pathway for RNA production so once you get UTP it can be processed into CTP by the enzyme CTP synthase and utilizing ATP in glutamine then this enzymes actually inhibited by CTP so it's a negative feedback regulation on the enzyme and these two UTP and CTP can actually used for RNA synthesis remember guys uracil and cytosine are used for RNA synthesis and this is where it actually is coming from so once you have CTP what can happen is it'll be converted to CDP and then it can be processed by the same enzyme as before ribonucleotide reductase into d CDP deoxy CDP this enzyme I didn't mention before but is regulated by a couple different things it's inhibited by D ATP and it actually requires a coenzyme known as die or a dachshund and now dcdp can be converted by a couple steps back into D unp or can be processed into D CTP and both dttp and dctp can be utilized for DNA synthesis so that is the de novo synthesis of permanence but primitives can actually be reprocessed or re synthesized from all primitives they can actually be salvaged in the cell now what can happen is DNA can any breakdown of DNA can release cytosine or thymine cytosine can be converted into uracil by deamination process releasing an NH 4 plus your so can likewise come from RNA as well but once you have these these products that the cell is very smart it can actually recycle them again and utilizing a couple of a couple of cofactors one for your cell your cell requires ribose one phosphate thymine requires deoxyribose one phosphate uracil and rivals one phosphate can can convert it into uridine by uranium phosphorylase and then by by the enzyme nucleoside kinase can be converted into unp whereas the thymine reaction can be the thymine plus deoxyribose one phosphate can get converted into thymidine by thymine phosphorylase and then into dtmp by the enzyme nucleoside kinase so these u n p and d TMP can be reprocessed and reutilizing the pathway just showed you guys in the previous slide and so this is another way the cell can actually recycle and resynthesize and reprocess these to utilize them again in the permitting synthesis pathway so you may be thinking okay why do we even need to do de novo synthesis of proteins anyway if there this can be salvaged well the problem is that these cofactors rivals one phosphate and deoxyribose one phosphate are at very low levels in cell so they actually aren't around they're not abundant they are not around to be utilized for this salvage pathway which means the salvage pathway doesn't actually operate at full capacity it can never operate at full capacity because these cofactors are at low amounts so we have actually limited salvage of primitives so that is why we need to actually have de novo permanent synthesis so anyways guys that was the video on permitting synthesis and metabolism I hope you guys found it helpful if you did please like and subscribe for more videos like this one and as always thank you so much for watching and have a great day