welcome to section 10 of metabolism in this section we'll be discussing the hexos monophosphate shunt also known as the hmp shunt this is also sometimes referred to as the pentose phosphate pathway let's get started the hmp shunt has two key functions first it produces nicotinamide adenine dinucleotide phosphate or nadph this molecule has several important functions it's involved in the synthesis of cholesterol steroids and fat it also protects the cells from oxidative stress which we'll talk more about in a minute and finally it assists phagocytic cells by generating nadph which is used in the respiratory burst the second function is the production of ribose 5-phosphate which can be used to synthesize nucleotides okay with this in mind let's look at the pathway this is the metabolic map provided in Section 1 of metabolism in this video we're focusing on the hmp shunt this pathway can be seen right here many of the pathways occur in the cytoplasm and the mitochondria however the hmp shunt occurs exclusively in the cytoplasm this is important because if you are given a list of enzymes you'd be expected to know which are only present in the cytoplasm versus which are present in the cytoplasm and the mitochondria okay let's zoom up on the pathway this is a detailed figure of the hmp shunt which can be found in section 10 of metabolism there are several reactions that occur in this pathway but you really only need to be familiar with a couple steps notice that glucose 6-phosphate is shunted away from glycolysis in order to produce ribulose 5-phosphate so recall from the video on glycolysis that this portion of the pathway represents a part of glycolysis also notice that one of the enzymes involved in the conversion of glucose 6-phosphate II ribulose 5-phosphate is glucose 6-phosphate d hydrogenase or G6PD this enzyme is incredibly important because it's responsible for the production of nadph and it's the rate limiting step of the hmp shunt ribulose 5-phosphate can then be converted into ribose 5-phosphate by an enzyme that is relatively unimportant finally ribose 5-phosphate can then either be utilized in the synthesis of nucleotides or it can be returned to the glycolytic pathway in the form of fructose 6-phosphate notice that the conversion of ribose 5-phosphate to fructose 6-phosphate is catalyzed by the enzyme trans-ketolase this is an important enzyme because it requires thiamine or vitamin B1 as a cofactor this means that the activity of the hmp shunt can be decreased in patients with a thymine deficiency also notice from the pathway that there are two arrows going between fructose 6-phosphate and ribose 5-phosphate there's an intermediate here but it It's relatively unimportant so it hasn't been included okay with this in mind let's discuss some of the key roles of nadph so again nadph has three major functions as I briefly mentioned at the beginning of this section let's discuss reductive synthesis first this is a figure from the section on fatty acid metabolism notice that nadph right here is required for the conversion of malonyl COA to fatty acids therefore patients with a G6PD deficiency may be unable to properly synthesize fat okay now let's discuss how nadph protects cells from oxidative stress this is a figure showing the interplay between glutathione and nadph which can be found in section 10 of metabolism glutathione is present in red blood cells and protects the cell from oxidative damage there are many triggers that result in oxidative damage some of these include fava beans sulfa drugs or infections regardless of the trigger hydrogen peroxide is produced in the red blood cells so I've shown here that fava beans sulfa drugs or infections can trigger the production of hydrogen peroxide in red blood cells the enzyme glutathione peroxidase neutralizes the hydrogen peroxide into water and generates glutathione disulfide in order for glutathione to be regenerated nadph must be used notice that glutathione reductase uses nadph to regenerate glutathione so in patients with a G6PD deficiency nadph cannot be produced and thus glutathione cannot be regenerated so red blood cells experience an increase in oxidative stress in the form of hydrogen peroxide which results in hemolysis so patients with a G6PD deficiency will have decreased nadph which will result in decreased glutathione which will result in hemolysis okay let's do a question a 24 year old male develops jaundice due to hemolytic anemia after digesting fava beans a blood sample is drawn which reveals the presence of bite cells what mechanism explains the formation of these cells hopefully from the question stem you notice that this patient has a G6PD deficiency we can deduce this because he digested fava beans which are a form of oxidative stress which then resulted in hemolytic anemia from the hmp shunt pathway we can see that a deficiency of G6 PD results in decreased nadph from this figure we can see that decreased nadph results in a decreased ability to regenerate glutathione this means hydrogen peroxide is not able to be neutralized the hydrogen peroxide reacts with hemoglobin resulting in conglomerates of oxidized hemoglobin these are also known as Hinds bodies as these red blood cells travel through the spleen the Hinds bodies are removed by splenic macrophages which results in red blood cells that look like someone took a bite out of them these are called bite cells so as the Heinz bodies go through the spleen the splenic macrophages damage the red blood cells resulting in the formation of bite cells okay now let's discuss how nadph assists phagocytic cells recall from Immunology that phagocytic cells such as neutrophils and monocytes use oxygen to create a superoxide anion this can then be converted into hydrogen peroxide and then bleach these substances can be used to kill bacteria the conversion of oxygen to a superoxide anion is catalyzed by nadph oxidase and requires nadph so I've shown that nadph is converted into nadp plus thus patients with a G6PD deficiency will be unable to generate nadph and the respiratory burst will be affected resulting in a weaker immune system okay let's do another question a patient has glucose 6-phosphate dehydrogenase deficiency but is still able to synthesize nucleotides what compensatory pathway explains this phenomenon okay let's pull up the hmp shunt Pathway to answer this question notice that a deficiency of G6PD will result in D increased ribulose 5-phosphate this is because this part of the pathway is irreversible notice the arrows which are only going in One Direction however the lower part of the pathway shown right here is reversible this means that even without ribulose 5-phosphate cells will be able to convert fructose 6-phosphate into ribose 5-phosphate which can then be used to synthesize nucleotides so in answer to our question patients with a G6PD deficiency will still be able to synthesize nucleotides due to the activity of the reversible part of the hmp shunt