welcome back to dirty medicines dirty biochemistry series this video is part two of the mini series and what I mean by that is that this is the follow-up video to the video that you probably just watched on the HMP shunt also known as the pentose phosphate pathway as I alluded to in the beginning of that video this is the second part of a biochemical process that is very closely tied to the HMP tion as a quick refresher in that part one of the HMP shunt video we discussed how NADPH is generated by the HMP shunt we talked about the one step that you should know how it's generating NADPH and that that NADPH would be very closely tied to what we're going to talk about in this video in part 2 about glutathione reductase let's jump right into part two and complete your understanding of not only everything that we talked about with the HMP shunt but also transition to glutathione and free radicals so in this video we're gonna be talking about glutathione reductase now this pathway it has one goal and it's to reduce glutathione now sometimes this pathway is referred to as the glutathione pathway other times it's referred to as the glutathione reductase pathway but technically speaking glutathione reductase is an enzyme so it's a little silly to name a pathway after an enzyme so if you hear me use the word glutathione reductase pathway or glutathione pathway or free radical pathway I'm talking about the same thing okay so this is the glutathione pathway and it's only goal is to reduce glutathione now let me turn your attention to a slide that we had in the first video on in the HMP shot we said that free radical detoxification requires reduced glutathione so obviously in this glutathione pathway the reason that the goal is to reduce glutathione is to be able to process and detoxify free radicals and peroxides now again just to really complete the whole picture it was free radical detoxification required reduced glutathione and in this pathway I'll show you how we actually reduce that glutathione but that required any pH which came from the HMP shunt so that is why all of these pathways are tied together now here's what you need to know about the glutathione reductase pathway so you start with oxidized glutathione right so you have glutathione and it's just existing in an oxidized form but that's not good because the body in order to make use of its normal physiologic biochemistry needs it to be in its reduced form so the enzyme that reduces oxidized glutathione to reduced glutathione is glutathione reductase and I mean how beautiful is this just look at the name of the enzyme glutathione reductase or reduce taste so it's reducing glutathione so it tells you that glutathione reductase is reducing glutathione so it's once glutathione is in its reduced form that it can actually go ahead and carry out its true biochemical purpose and that is to say that reduced glutathione will proceed to detox the body against free radicals and to detox the body against peroxide okay so in this very simplified image what you see is reduced glutathione positively converting peroxide into water and also in green text handling free radical detoxification so glutathione is a very potent free radical detoxifier and it's the reduced form of glutathione that we need in order to protect the body against free radicals so if you were half paying attention to anything in the first two years of medical school you probably understand that free radicals are very serious and it's when the body cannot process or detoxify those free radicals that cellular damage occurs so again if I can sort of take a step back and pause for just a second what I'm telling you is that the glutathione pathway has one goal it's to reduce glutathione and that reduced glutathione will go on and chop up all the free radicals that could potentially cause really bad damage and disease in the human body so that's the normal biochemistry and again that process of getting reduced glutathione depends on the HMP shunt now let me tie this all together in this step where the enzyme glutathione reductase is happening NADPH is actually being converted back into nadp+ and this is interesting right because I told you that the goal of this pathway was to reduce glutathione but we need NADPH to do that so we need an input of NADPH in order to reduce glutathione so where do we get that input of NADPH well this is the connection between the HMP shot and the glutathione pathway we're taking the NADPH that was generated here in the HMP shunt and we're plugging that NADPH in to the glutathione pathway and connecting these wheels if you will so what you see is constant spinning or constant wheels where these two pathways are interacting with one another in a very cyclical form so what you're seeing on this slide is a very simplified version of the connection between the HMP shot shown on the left and the glutathione reductase pathway shown on the right - one - once again summarize because I cannot stress enough how high-yield this is glucose 6-phosphate dehydrogenase will take glucose 6-phosphate which it stole from glycolysis and convert it into six phosphoglucomutase for nadp+ then glutathione reductase sees that NADPH sitting there and it goes Foom I need that NADPH in order to reduce glutathione and reducing glutathione is of the utmost importance because again the body needs reduced glutathione in order to handle free radicals so that the glutathione reductase will grab that NADPH that the HMP shunt generated and it will use it to make reduced glutathione and of course when it makes reduced glutathione one of the end products that the glutathione pathway spits out is an nadp+ which the HMP shot looks at and says okay now I'm going to keep going and you've got the cyclical wheel if you will that just keeps spinning so this is the connection between the HMP shunt and the glutathione reductase pathway now what happens if cells lack NADPH right that is to say what happens if this wheel stops spinning because one of the inputs is no longer there well I'm going to show you in purple what would happen let's say that you don't have NADPH and for now don't worry about why you don't have it but if you don't have NADPH then you get a decrease of reduced glutathione because glutathione reductase can only reduce glutathione if it also converts NADPH to nadp+ so a decrease of NADPH means a decrease in reduced glutathione and of course a decrease in reduced glutathione means an increase in oxidative stress and this is really serious when free radicals go unchecked and there's increased oxidative damage in the body disease will occur so the question is what causes oxidative stress well we've got a few different causes there are sulfa drugs the drug primaquine infections or any kind of illness nitro fear and toen another antibiotic and PHA the beans kind of random I know about favor beans so how do you remember the causes of oxidative stress well what I want you to remember is spin F or spin off so instead of saying spin off I say spin off' spin F and the reason that spin F reminds me of these different causes of oxidative stress is that spinning is what a wheel does and I remember the little wheel or the cyclical nature of the HMP shot and the glutathione reductive reductase pathway so again how how do you remember that this mnemonic correlates to oxidative stress well I remember the spinning of the wheels in the HMP shunt and the glutathione pathway then I remember spin off and spin fs4 sulfa p4 prema queen I for infection and for nitro fear aunt Ellen and f4 favored beans so these are the things that cause oxidative stress and this is really significant because as we're going to see in just a moment in certain people who lack an enzyme these insults that cause more oxidative stress that the body could normally handle just fine will actually go unchecked and cause so much oxidative stress that you're gonna get really severe anemia so let's come back to the question what happens if cells lack NADPH well let's talk about one major cause of that so one way that cells can lack NADPH and be really susceptible to the that I just showed you on the last slide that caused significant oxidative stress is if you knock out glucose 6-phosphate dehydrogenase so those who have a deficiency of glucose 6-phosphate dehydrogenase obviously cannot generate NADPH from nadp+ and this is a problem because when we can't generate NADPH glutathione reductase can't make reduce glutathione and if we don't have reduced glutathione you have oxidative damage from free radicals so the very high yield disease that I'm talking about is a g6pd deficiency now this is an x-linked recessive disease and the findings we've already talked about right you can't make NADPH so you get no reduced glutathione no reduced glutathione needs increase oxidative stress so what else are really high yield findings that you should be familiar with well in a g6pd deficiency you're gonna see what's referred to as Heinz bodies and Heinz bodies are just little clumps of denatured hemoglobin that are going to accumulate inside of a red blood cell the more oxidative damage going on inside of a red blood cell means the more cellular components get damaged so hemoglobin gets damaged and denatures into these little teeny balls that you can see inside of the RBC that is referred to as a Heinz body now what happens next macrophages that are sequestered by the spleen will come out and say huh that's weird what are those little denatured hemoglobin balls doing in the red blood cells I need to get rid of them because after all a macrophages job is to eat foreign particles that should not be present in cells so macrophages flunk'd from the spleen will bite off little chunks of the red blood cell and when it does that all it's trying to do is get rid of that denatured hemoglobin right it's trying to get rid of the Heinz bodies but in doing so it leaves what are called bite cells so bite cells as the name implies are literally when macrophages from the spleen take bites out of the red blood cells now this is an attempt by the body just to undergo phagocytic clearance right all it wants to do is clear out the Heinz bodies but in doing so it's breaking the red blood cells and literally taking a bite out of it so again picture take a step back and pause for a second anybody who does not have the enzyme glucose 6-phosphate dehydrogenase has by definition a g6pd deficiency this is an x-linked recessive disease where you lack the key enzyme in the HMP tion that usually generates NADPH if you can't generate NADPH and therefore can't make reduce glutathione and therefore can't handle oxidative damage from free radicals in the body then you're very susceptible to hemolysis when your red blood cells undergo oxidative damage and it's from those agents that we talked about in the spin F mnemonic that could possibly introduce oxidative stress because those agents are oxidizing in nature now again normally a regularly functioning person with this enzyme would be able to handle that stress with no problem but in those who are deficient in this enzyme that oxidative insult gets really out of control and you can get really profound anemia so if on your exam you see a vignette where all of a sudden somebody eats a random bean right a favor bean and they undergo labs or a clinical picture that looks like severe hemolysis this is your answer if somebody started on an antibiotic such as nitro if you're in toen or a sulfa drug of any class and all of a sudden they're having anemia this is your answer it's especially high yield to know these pictures because instead of describing what I just said in the clinical vignette they could very literally just show you Heinz bodies the denatured hemoglobin or the bite cells the attempt at the splenic macrophages to clean up those signs bodies and expect you to know the pathophysiology that we're talking about so as you can see glucose 6-phosphate dehydrogenase deficiency is a very high yield biochemical disease now how do you remember all this stuff right I've just given you a ton of information and if anybody has watched any of my videos you guys know that I don't want to overwhelm you and my only concern is that you do really well on test day so I've got a really awesome dirty medicine pneumonic to remember all of this stuff so when I say g6pd deficiency or when I think about a g6pd deficiency I think about 6g PD so I just kind of reorder it a little bit instead of g6pd I think of 6g PD and what that reminds me of is the number six Gorder pounder so if you've ever gone to a Burger King McDonald's whatever you can order you know the number one the number two the number four the number six whatever and they have quarter pounders right that's a burger in the United States so I think about Gorder pounder so instead of quarter I just changed that cue to a G so my pneumonic is take a bite of the number six Gorder pounder or quarter pounder if you will with heinz ketchup right Heinz is the like number one ketchup brand in the United States so take a bite of the number six quarter pounder with Heinz ketchup what does this tell you well bite for bite sells six GPD for g6pd and Heinz ketchup for Heinz bodies so this is giving you all the high-yield associations and tying it in to the disease so this is it guys this is the slide you need to keep in mind this is the big picture right the combination of the HMP shunt working in tandem in this cyclical way where the wheel keeps spinning working with the glutathione pathway again the common goal here is to handle free radical and oxidative damage but individually the HMP shunt generates NADPH and the glutathione reductase pathway reduces glutathione it keeps on working together there's this beautiful synergy here and this is the biochemistry that you absolutely need to know this is very very high yield and I think that I've done a good job of explaining it so watch this video a few times if you need to but if you're comfortable with all of this material and you'll be able to answer most if not all of your questions on USMLE and comlex