what's up everybody in this video i'm going to teach you everything that you need to know about the heme synthesis pathway and all associated diseases this is brought to you by dirty medicine dirty i love what you do on this channel how can i give back well thank you for asking if you're looking for a way to support my channel financially you can click the join button that join button is found underneath every single video and it's also the first link in the description of any video on my channel when you click that join link you'll sign up to be a dirty medicine member which means that you'll pay 4.99 a month in financial support of my channel in exchange for a few cool perks i really appreciate your consideration so if you want to give back that's the way to do it now let's get into today's video this video is about heme synthesis and there's a lot of confusion and a lot of anxiety when it comes to learning the heme synthesis pathway because unlike other pathways in biochemistry the heme synthesis pathway has the pathway itself so of course you need to know things like products reactants enzymes but then you also need to know at what point in the pathway certain diseases will manifest if there's a problem with a particular enzyme to make matters even more complex a lot of these diseases have a lot of overlapping features the words sound the same and a lot of medical students just have nightmares when it comes to this topic so my goal in this video is to first go through the pathway as we normally would as if we were approaching this like a biochemistry pathway i'll point out what you need to know and then i'm going to simplify and reduce everything using some helpful mnemonics and pointing some things out to you so that you're able to conceptualize this and answer 100 of your questions with ease so with that said let's get started before we go anywhere i want to point out that when we talk about the heme synthesis pathway part of the pathway occurs in the mitochondria so that'll be the left part of this slide and part of the pathway is occurring in the cytosol so that'll be on the right part of the slide now where we begin is with the two reactants glycine plus succinyl coa and these reactants will go to the product aminolevulenic acid also known as ala the enzyme that does this reaction is actually our rate limiting enzyme that's ala synthase so right off the bat the first step of the pathway is the rate limiting enzyme which makes it a little bit easier to memorize because you don't have to worry about an enzyme that's like halfway down so glycine plus sextinal coa going to ala by ala synthase this should be somewhat easy to remember because ala synthase is synthasing or synthesizing aminolevulinic acid and you can see here that vitamin b6 shown in blue is a cofactor so this is a very important step and probably the highest yield step in the whole pathway so the first step is our rate limiting step now it's amino levulinic acid that actually leaves the mitochondria and enters the cytosol and the conversion of ala into something called porphobilinogen is done by ala dehydratase so ala leaves the mitochondria and then in the cytosol gets converted to porphobalinogen porphobilinogen will that get will then get converted to hydroxymethylbiline and that's done by porphobilinogen deaminase and then hydroxymethylbyline will be converted to euro perferinogen 3 and i don't care that you know this step it's not really important and i'll explain why in a little bit uropharynogen 3 gets converted into copro porphyrinogen 3 and the enzyme that does that conversion is euro porphyrinogen decarboxylase now at this point the coproporphofarinogen3 will travel back into the mitochondria so we've been in the cytosol for the past three or four steps now we're going back into the mitochondria and the copro pharynogen 3 will get converted to protoporphyrin and again i don't care that you know that step because you don't need to know the enzyme again i'll explain why in a little bit and then once we're back in the mitochondria the proto-porphyrin gets converted by ferocitase into heme using iron as a cofactor okay so these are all of the steps of the pathway this is the entire pathway from start to finish the first step is in the mitochondria then ala leaves the mitochondria we have a couple more steps getting to copro porphyrinogen three and then copro porphyrinogen three goes back into the mitochondria there it gets converted to proto-porphyrin and then that goes to heme and that's how we make heme hence the name heme synthesis pathway now the first thing that i want to point out that's very important to understand for usmle and comlex is that you need to know what steps occur in the mitochondria and what steps occur in the cytosol and i think that the easiest way to memorize that is to simply memorize the two parts where there is the leaving or entering of one or the other so what i'm talking about is that aminolevulinic acid that leaves the mitochondria and goes into the cytosol so you would know if you were somehow able to memorize that that the next several steps are in the cytosol and then copropharynogen goes back into the mitochondria so if you were able to memorize that then you would know that everything that came after that was happening back in the mitochondria so what i'm saying here is that we need a mnemonic to memorize those two steps because those two steps are the transition points in this pathway and the way that i memorize this is that i for ala i say i'm going allah cytosol so that means to the you know in a lot of uh in like spanish i'm going allah cytosol and then for copropreferinogen i say caught me some mitochondria which reminds me that it's the uh the reactant that starts with cop that goes back into the mitochondria so cop me some mitochondria cop for coproporaferinogen that's going back into the mitochondria and ala is going allah ala for allah it's going allah cytosol and that's how you know that it leaves the mitochondria and goes to the cytosol so if you're able to memorize that using those mnemonics then you really should understand where everything else in this pathway is occurring so here's where we are so far and what you need to do at this point is to simply understand the order of the pathway because after all it's probably not worth memorizing those two mnemonics that i just gave you if you don't know what comes after ala and you don't know what comes after copropharynogen so what i'd like to do is highlight the first letter of all of the reactants here i'm highlighting them in green as you can see on this slide and then what i'll do is if i can sort of just pull these off the slide and put them in order going down we have glycine succinyl coa aminolevulinic acid porphylbalinogen hydroxymethylbylane uroperferinogen3 copro porphofernogen3 protoporphyrin and then heme so this is the order of the pathway g s a p h u c p h and my mnemonic to remember the order of this pathway is that you can get some additional points having understood the correct pathway for heme boom easy peasy and it tells you exactly what pathway we're talking about because it ends with heme so you can get some additional points having understood the correct pathway for heme so that's your mnemonic to pair up with these reactants so that you understand the order and then remember the the other mnemonic going allah cytosol and caught me some mitochondria so that you know where the transition points are so at this point in the video you understand the pathway you know all of the enzymes and we'll come back to the enzymes in just a second you know the order of how the pathway proceeds because of that super awesome mnemonic and you know the transition points in this pathway going allah cytosol so allah leaves the mitochondria goes to the cytosol and then you know caught me some mitochondria so the reactant that starts with cop is the one that's going back into the mitochondria from the cytosol so a couple really high yield things are you understand already right off the bat the second part of this video and probably the higher yield part of this video is to understand at what point in this pathway will you get the manifestation of disease if one of these enzymes doesn't work so if you if i pause for a second and go back to the statement i made a few minutes ago i told you that there are a couple steps here that i don't care if you know the enzymes for and what i'm talking about is the ones where you don't see enzymes listed so going from hydroxymethyl biline to uropharynogen 3 and going from coproporpharynogen 3 to protoporphyrin you don't need to know those enzymes because there's no disease that happens when those enzymes don't work the really high yield diseases are what you get when some of the enzymes that you see on this slide don't work so there are five enzymes that you see here ala synthase which is our rate limiting enzyme ala dehydratase porphobilinogen deaminase euro porphyrinogen decarboxylase and ferrochelatase and at each of these enzymes if you have a dysfunction or a deficiency of these enzymes you get certain diseases and what's obviously really high yield for usmle and comlex is to know what those diseases are and to know what those diseases look like so when you see the associations in the clinical vignette you see the buzzwords you see the labs you see the hints and you see some high-yield images you know what disease they're talking about and then you could pick the correct enzyme so like a really classic question would describe for you one of the diseases and then ask you which of the following enzymes is dysfunctional and you'd have to pick either ala synthase all dehydrotase etc so let's go through these one at a time and talk about the different diseases that you get when these enzymes don't work so we'll just go in order so the first one is when ala synthase is dysfunctional you get citaroblastic anemia so the cause can either be due to a congenital cause and that's an x-linked deficiency of ala synthase but you can also get an acquired cause which either can be due to b6 deficiency since b6 is a cofactor alcoholism or lead poisoning and the really high yield association here is to know that isoniazid can cause b6 deficiency so if someone's taking isoniazid they can become deficient in b6 which means they don't have the cofactor required for the enzyme ala synthase to work and therefore functionally it's as if ala synthase itself is absent and that would cause citroblastic anemia now as far as the buzzwords or the clinical associations that you want to look for are concerned you want to look for images of ringed citroblasts and what you can see here is an example of a ringed citroblast and the reason that you get ringed citroblasts in citroblastic anemia is that basically citroblastic anemia is due to a problem where iron cannot be incorporated into heme so if we go back to our pathway here technically ala synthase deficiency gives you citroblastic anemia but even steps that occur after this first step can still give rise to citroblastic anemia because if you can never get proto-porphyrin converted into heme and in that step you sort of strap or attach the iron onto the protopurpurin to make the heme you get some symptoms of citroblastic anemia and the reason why you get a ringed citroblast is because if you're not able to attach that iron to the proto-porphyrin to make heme then that iron is just sitting in the mitochondria and when iron is just sitting in the mitochondria you see this in the cell so around the cell or in the cell rather you see iron that's just trapped in the mitochondria and that stains that kind of light blue color so that's the iron that's just sitting there and the reason that it's sitting there is again because of this ala synthase deficiency and therefore because way downstream of that first step you can never make heme iron can't be attached in the step that goes from proto-porphyrin to heme and therefore it's just chilling in the mitochondria so citroblastic anemia bottom line congenital due to x-linked ala synthase deficiency acquired because of the lack of that b6 cofactor which will usually be due to isoniazid the image will either show you a ringed citroblast where there's iron trapped in the mitochondria or they'll describe it to you as far as labs go because you've got iron sitting in the mitochondria the labs are going to resemble an iron overloaded state so you'll see an increased ferritin a decreased or normal tibc and increased iron treatment here is pyridoxine now the question is how do you remember how do you memorize that citroblastic anemia is due to an ala synthase deficiency and the way that i remembered this is that the the initials for citroblastic anemia are sa and sa backwards is a s so ala synthase so s-a-a-s-s-a for ala synthase kind of easy so that's the first one that's the first disease you get if one of these enzymes don't work now the next disease you actually get if two different enzymes don't work so for both ala dehydrotase and ferrochelatase if those enzymes don't work you get lead poisoning so the cause of lead poisoning is due to each of these enzymes not working or one of these enzymes not working but the question is what is it that makes these enzymes not work and usually that's an environmental exposure so in children that's going to be exposure to lead paint and in adults it's going to be an environmental exposure usually where the adult is working so look for things like batteries ammunition or water in old lead pipes okay now the big association for lead poisoning is going to be an image and that's going to be an image of basophilic stippling and when you you look on this slide you can see what basophilic stippling looks like and these are like little teeny granules in the cell that is due to some product some residual products of rna ribosomes mitochondria and citrosomes and they get clumped up in these little clusters and they just sit in the cytoplasm due to the toxic effect of lead poisoning the other associations there's two more that you need to look for so not only basophilic stippling but also these things called lead lines so if you're answering a question that kind of feels like it's about a heme synthesis pathway and then they show you an x-ray specifically they show you a long bone and you see these little lines i know that medical students like generally speaking don't know how to read x-rays but if you see these lines on long bones these are called lead lines they're right right in the metaphysial region and this is due to lead deposition in the zone of calcification of the bone so this is a really classic sign of lead poisoning the last one is called a burton line a burton line is just this blue black discoloration along the base of the gums so if you see an image of teeth you see an x-ray or you see a cell those are all linked or associated with lead poisoning so think lead poisoning now again the question is how do you memorize that lead poisoning is a problem with fear alkylatase and ala dehydratase and my mnemonic is to write those two enzymes out and instead of fearoculatase i say lyroculotase and then the first two letters of each of these makes lead l-e in lirokilatase and the a and the d from ala dehydrotase l-e-a-d for lead poisoning so here's where we are we know that citroblastic anemia is due to ala synthase deficiency because sa is a s backwards and we know that lead poisoning l-e-a-d for lyrokilatase which of course is spheroculatase and ad for ala dehydratase so it's not as complex or not as confusing as a lot of these review sources would make this seem now let's talk about our next disease so if porpho excuse me porphobilinogen deaminase is dysfunctional you get acute intermittent porphyria so in this disease really the association is all you need to know this is the one that they say the five ps which is kind of an overstated uh mnemonic here but the five ps stands for pain in the abdomen polyneuropathy port wine colored urine p450 inducers and psychological symptoms really the big thing here is you're going to get a test question on usmle or comlex they're going to describe somebody with gi pain of course at first glance your brain is going to go to the gi section and start to think of all that stuff but they're going to connect it to the heme synthesis pathway by giving you these weird symptoms so it's going to be like neuropathy gi pain maybe it'll be some neuropsychiatric symptoms and then they're going to ask you either for the enzyme which of course would be porpolenogen deaminase the buildup or they're going to ask you what caused this and the high yield one that i really want you to know are the p450 inducing medications so a couple of the big ones are phenytoin barbiturates and sulfonamides but basically what's happening here is when somebody takes one of these medications not only does it induce the cyp450 enzyme but it induces ala synthase as well and if we go back to our pathway here i'm sure you can appreciate that if ala synthase gets induced which means it kind of shows up and starts acting and it tries to send this pathway forward but somebody has acute intermittent porphyria and therefore porphobelinogen deaminase does not work you're basically creating a build-up of porphobalinogen that can't get converted to hydroxymethylbiline and in acute intermittent porphyria the reason that somebody gets gi pain polyneuropathy neuropsychiatric symptoms is because porphylobalinogen is very neurotoxic so it irritates somebody's stomach it irritates somebody's brain etc so if you give somebody a medication that induces ala synthase and tries to turn on this pathway that makes acute intermittent porphyria worse so bottom line here is when you get a question on usmle or comlex and they talk about one of those p450 inducing medications at first glance it might seem like a pharmacological question something about mechanisms side effects but really what the test writer might go after is acute intermittent porphyria so again just like all of our other examples here the big question is how do you remember that acute intermittent porphyria is linked to the dysfunction of porphobilinogen deaminase and the way that i encourage you to remember this my mnemonic is that aip instead of aip for acute intermittent porphyria i say aipd and the pd stands for porphobelinogen deaminase so acute intermittent porphyria aipd pd for porphobelinogen deaminase now we've only got one enzyme left and that's euro porphyrinogen decarboxylase and if that enzyme is dysfunctional you get porphyria cutanea tarda so pct is actually a really easy one to remember and the the reason that it's so easy to remember is that in the name it has cutanea or cutaneous so you know that this has something to do with the skin now the cause here as i just said is a uropharynogen decarboxylase dysfunction the high yield associations mostly have to do with the skin because again the disease has cutaneous in the name so you get hyperpigmentation blistering and photosensitivity those are the big three symptoms but you also want to know that this is associated with hepatitis c and that this is worsened by alcohol treatment is phlebotomy and low-dose hydroxychloroquine of all the diseases porphyria cutanea tarda is the one that's the the lowest yield that i think has the least complex and least high-yield associations to it so if you're kind of like figuring out what's important and what you really want to focus on in this video this can be at the bottom of your list but i've got great news for you guys that's it that's the heme synthesis pathway it's not as big and scary as all these other resources make it seem like you don't need a 60 minute long video to explain this it's a rather straightforward pathway with a few important enzymes and a few important diseases but if you use my mnemonics and you keep everything stupid and simple literally that's how i get through my day every single day keep it stupid keep it simple you're gonna understand this whole pathway you're going to get 100 of the questions right and i just don't want you guys to be scared so i hope that this was useful to you if you enjoyed this video please share with your friends i'm so tired of seeing people waste their medical school loan money on these overpriced click bait resources so please get this out there share this with people that are in dedicated again i hope it was useful love you all