Pyruvate Pathways & Metabolism

welcome back to dirty biochemistry in this lesson we're going to discuss the pyruvate molecule and how it is the most important molecule in determining which end product and which reaction pathway we ultimately choose to take this lesson is on pyruvate metabolism as a brief refresher in the last lesson we discussed glycolysis and gluconeogenesis when you start with glucose and ultimately form pyruvate downstream that is glycolysis shown here in red if instead you move in the reverse direction starting with pyruvate and going up to glucose that is gluconeogenesis shown here in blue now that we have

that brief refresher in mind we need to talk about what we can actually do with pyruvate now I want you to think about pyruvate as the jack-of-all-trades it is one of if not the most important molecules in any of these biochemical pathways because pyruvate can at any point in time change itself or transform itself through a chemical reaction into one of four different products so in all of these next examples where we're going to go through four different biochemical pathways we're gonna start with the reactant of pyruvate and ultimately be able to form four different

end products the first pathway that pyruvate can take is to turn itself into lactic acid aka lactate when it does this we're talking about the pathway referred to as anaerobic glycolysis now the word anaerobic means in the absence of oxygen and aerobic there is no oxygen this is glycolysis occurring without the presence of oxygen now normally oxygen is hugely important in the ability to conduct glycolysis recall that glycolysis and all metabolic pathways have one goal in mind and that is to work in tandem to form cofactors and reactants that can be used with one another

to ultimately send everything to the electron transport chain to generate a massive amount of ATP now I want to take a step back and think about the big picture here we have several different pathways and you need to know several different pathways which will all be covered in this lecture series there's glycolysis gluconeogenesis the krebs cycle aka the TCA cycle there is different protein formation and fatty acid synthesis but I want you to relax for a second and keep the big picture in mind all of these different pathways are working in tandem to form molecules

that will ultimately all be shunted into the electron transport chain where you generate the most massive amount of ATP that is the job of biochemical reactions occurring in the body so if we keep that in mind and remember that oxygen is the ultimate or final electron acceptor in the electron transport chain it should come as no surprise to you that in the absence of oxygen which is to say that the electron transport chain will simply not work there's no point in going through regular glycolysis in this case we're going to shut pyruvate through anaerobic glycolysis

because there's no point in doing regular glycolysis again because without oxygen you don't have the final electron acceptor in the electron transport chain so it's just a wasted reaction now with that in mind it should make a little bit of sense why instead of going from glucose to pyruvate and then sending pyruvate to the TCA cycle we're just going to convert pyruvate to lactate acid and that's done in the anaerobic glycolysis pathway which is going to be the first pyruvate pathway that we talked about today so I know that that was a pretty extensive aside

but I really want you to keep the big picture in mind because when you get lost in these details you lose focus of what the actual purpose of these reactions are in the body so the conversion of pyruvate to lactate acid is what's termed anaerobic glycolysis and the enzyme that does this reaction is called lactate dehydrogenase or LDH for short now this enzyme is active in certain conditions and I've already told you that this is anaerobic glycolysis so it should come as no surprise that the main condition in which LDH is active is in low

oxygen State now clinically low-oxygen states occur in things like infection hypoxia ischemia and heart failure so when you ultimately become an upper-level student and you go into the hospital you will not be surprised to learn that in states such as these we obtain lactate levels when we test people's blood because an elevated lactate is telling us that the patient does not have adequate oxygenation and it use us that there may be some underlying infection or some underlying hypoxic or ischemic event going on now in certain tissues this is the pathway that pyruvate will primarily go

through and those tissues are shown here the testes the lens white blood cells the cornea the medulla of the kidney and red blood cells this is simply a laundry list that you need to memorize but I have a mnemonic to make it a lot easier for you so I want you to think lactate when you can't make respirations so when you can't make respirations which is to say that you don't have access to oxygen you will undergo anaerobic glycolysis and shunt pyruvate into lactic acid so the mnemonic here is think lactate when you can't make

respirations t4 testes l4 lends W for white blood cell C for cornea m4 medulla of the kidney and R for red blood cells if you remember this mnemonic you can remember all of the tissues where anaerobic glycolysis has a propensity to occur now in closing really briefly I want to mention that the cofactor in the reaction catalyzed by lactate dehydrogenase is vitamin b3 and in all of these situations if there is a cofactor that's worth remembering I'll include it briefly on the slide but that is the first possible pathway for pyruvate the next possible pathway

for pyruvate is actually being able to be turned into alanine this conversion is referred to as the alanine aminotransferase pathway and the enzyme that converts pyruvate to alanine is alt the cofactor here is vitamin b6 now you may be asking yourself why would we want to turn pyruvate into alanine and the reason is something called the Cahill cycle so pyruvate is not able to jump between muscle and liver it's simply unable to do it so in order to recycle carbons between the muscle and the liver we actually have to disguise pyruvate as alanine or glucose

to be able to make this a possibility so let's take a second and show you exactly what the Cahills cycle is and why it's such an advanced adaptation that is really remarkable thing so here on the left you see a liver and here on the right you see a muscle obviously I'm simplifying these drawings to show you some biochemical pathways so starting with pyruvate you can turn pyruvate into alanine using the alt enzyme that I've shown you on the previous slide this conversion will also use up glutamate and spit off alpha ketoglutarate you need to

memorize these are cofactors so it's pyruvate plus glutamate goes to alanine plus alpha ketoglutarate since pyruvate cannot jump between muscle and liver alanine can that is why we convert the pyruvate into alanine once you have the alanine the alanine can go from the muscle into the liver sneaky little alanine alanine once it's in the liver can be converted back into pyruvate using alpha key to glute irate and spitting off a glutamate so it's the same reaction in the muscle just backwards once we have the pyruvate we need to get the pyruvate back over into the

muscle so that we can keep the cycle going but I told you that pyruvate cannot jump from liver to muscle or from muscle to liver so how do we accomplish this well in the cahill cycle we actually hack the system and use gluconeogenesis which you already learned about in the first lesson so we go back up from pyruvate to glucose and that's just gluconeogenesis folks once we have the glucose the glucose can jump from the liver to the muscle and then once in the muscle we use glycolysis to go down from glucose to pyruvate talk

about an amazing system look how awesome that is the red arrows shown on this slide on the left in the liver going from pyruvate up to Lucas that is just gluconeogenesis which you've already learned about and then on the right in the muscle the red arrow going down from glucose to pyruvate that's just glycolysis and you already know that so it's really the glucose and the alanine that's able to move between liver and muscle to bring pyruvate across your muscle to liver and the whole reason that we do this is because pyruvate is a carbon

molecule and we need to move those carbon molecules around to make use of certain materials in the body so this is the reason that we turn pyruvate into alanine it's to make use of the cahill cycle now the cahill cycle itself refers to everything you see here with red arrows it's the constant conversion from pyruvate to alanine from alanine back to pyruvate from pyruvate to glucose from glucose back to pyruvate that cycle continues indefinitely while we regenerate glutamate and alpha-ketoglutarate on the side and use them as cofactors this is the cahill cycle now that's the

reason that we would convert pyruvate to alanine and to quickly summarize so that you don't get lost from pyruvate to lactate acid is anaerobic glycolysis which occurs in low oxygen States from pyruvate to alanine that is to shunt around and cycle carbon molecules using alt through the cahill cycle the next option for pyruvate is to be converted into oxaloacetate and the enzyme that does this conversion is pyruvate carboxylase using a cofactor of biotin now we're not going to talk about this pathway too much but the goal here is to use oxaloacetate as an available reactant

for either gluconeogenesis and/or the TCA cycle oxaloacetate can contribute to gluconeogenesis but also the TCA cycle truth be told this is really just a fail-safe in case the body needs to generate an additional reactant to push it in either direction of gluconeogenesis or the TCA cycle so pyruvate has a lot of jobs and one of them is to use pyruvate carboxylase and biotin as a cofactor to generate oxaloacetate to simulate gluconeogenesis or the TCA cycle in certain situations that's really all you need to know about that pathway from pyruvate not too much to know but

just something to keep in mind the final and perhaps most important pathway for pyruvate is its ability to be converted into acetyl co a the reason that this is so important is because acetyl co a is the chief reactant of the TCA cycle so without the conversion of pyruvate to acetyl co a we would never be able to complete TCA cycle now the enzyme that converts pyruvate to acetyl co a is pyruvate dehydrogenase not only should you memorize pyruvate dehydrogenase but you also need to memorize the five cofactors vitamin b1 vitamin b2 vitamin b3 vitamin

b5 and lipoic acid please please please memorize this it is extremely high yield now I told you acetyl co a is the chief reactant of the TCA cycle so if you never convert pyruvate into acetyl co a then you can never provide the reactant for the TCA cycle to spin the TCA cycle and generate the carbon dioxide necessary to carry out a series of reactions that in unison across all reactions will ultimately make use of different products to go to the electron transport chain and generate massive amounts of ATP that's the big picture the last

thing that I want to point out is that you'll notice that in the reactions of going from pyruvate to oxaloacetate and from pyruvate to acetyl co a these are irreversible reactions they are one-sided arrows but going from pyruvate to lactate acid or pyruvate to alanine are reversible reactions and what you need to know about the differences here are that oxaloacetate and acetyl co a are formed from pyruvate in the mitochondria whereas pyruvate to alanine and pyruvate to lactate acid are formed in the cytosol please memorize that because occasionally test writers have been known to ask

you exactly where these reactions take place I want to pause for a second and subarrays the high-yield points from this lesson because there was a lot of information and they don't want you to get lost in the details glycolysis gluconeogenesis different types of synthesis whether it's fatty acids ketones or proteins all of the chemical reactions in the body work together to generate an interactive set of reactants products and cofactors that can ultimately go to the electron transport chain and generate a massive amount of ATP for the body we'll talk about the electron transport chain in

another video in this series but you should know right now that the job of the electron transport chain is like a gigantic machine that generates an enormous amount of energy for the body so all of these reactions have to find some way to work together to form everything needed to make that a possibility in low oxygen States where electron transport chain can simply not happen pyruvate will go to lactic acid in low oxygen states such as infection ischemia hypoxia and heart failure LDH catalyzes that reaction in other scenarios pyruvate will turn into alanine through alt

and the reason that we do this is to satisfy the Cahills cycles ability to recycle carbon molecules from the liver to the muscle and vice versa in some situations pyruvate can be turned into oxaloacetate using pyruvate carboxylase oxaloacetate can stimulate gluconeogenesis and it also has a secondary stimulating effect on the TCA cycle and lastly pyruvate can be turned into acetyl co a by pyruvate dehydrogenase with five important cofactors acetyl co a is the chief reactant in the TCA cycle and without the ability to convert pyruvate into acetyl co a it could never happen acetyl co

a and oxaloacetate are formed in the mitochondria whereas alanine and lactic acid are formed in the cytosol that's it for this video Arie watch it if you need to but pyruvate metabolism is extremely important