Pentose phosphate pathway (PPP)
It is also called a Phosphogluconate Pathway or Hexose Monophosphate pathway. In this pathway, NADP+ is an electron acceptor instead of NAD+. This is taking place in the two-phase- oxidative phase of PPP and non-oxidative phase of PPP.
Figure: The pentose phosphate pathway (PPP). The PPP branches after the first step of glycolysis and goes back to fructose 6-phosphate and glyceraldehyde 3-phosphate in the glycolytic and gluconeogenic pathway. The PPP produces R5P and NADPH for biosynthesis and redox regulation. Enzymes in the oxidative and non-oxidative PPP are shaded in green. Image Source: Front. Endocrinol., 09 June 2020 | https://doi.org/10.3389/fendo.2020.00365
The oxidative phase of the Pentose phosphate pathway
Step first – In the first reaction, glucose 6-phosphate oxidized into 6-phosphoglucono-delta-lactone in the presence of glucose 6-phosphate dehydrogenase enzyme, where NADP+ act as an electron acceptor.
Step second – In this step, 6-phosphoglucono-delta-lactone is hydrolyzed by specific lactonase into 6-phosphogluconate.
Step third – Now, oxidative decarboxylation of 6-phosphogluconate to D-ribulose 5-phosphate is taking place by 6-phosphogluconate dehydrogenase enzyme, and NADP+ act as an electron acceptor.
Step fourth – Now ribulose 5-P isomerizes into ribose 5-P by phosphopentose isomerase.
The non-oxidative phase of the Pentose phosphate pathway
Step five – Here, epimerization of ribulose 5-P to xylulose 5-P is taking place by ribulose 5-P epimerase.
Step six – Now ribose 5-P and xylulose 5-P react to yield sedoheptulose 7-P and glyceraldehydes 3-P in the presence of transketolase.
Step seven – Sedoheptulose 7-P and glyceraldehyde 3-P react to yield fructose 6-P and erythrose 4-P.
Step eight – Now erythrose 4-P and xylulose 5-P react to yield fructose 6-P and glyceraldehyde 3-P.
Step nine – In this step, fructose 6-P isomerizes into glucose 6-P by phosphohexose isomerase enzyme.
Step ten – In this step, glyceraldehyde 3-P enter into gluconeogenesis and convert into glucose.
Glucose 6-P dehydrogenase deficiency
Glucose 6-P dehydrogenase deficiency mostly asymptomatic; symptoms appear only with a combination of several environmental factors. The Greek mathematician Pythagoras prohibited his follower from eating favabean (falafel a dish has fava bean as an ingredient also prohibited) because this makes many people sick with a condition called favism, in which erythrocytes lysis takes place within 24-48 hours, free hemoglobin released into the blood, causing jaundice and sometimes lead to kidney failure, antimalarial drug primaquine or sulfa antibiotics also give the same symptom in glucose 6-P deficient persons. The NADPH produced in the first reaction of PPP by glucose 6-P dehydrogenase, this NADPH used in several biosynthetic pathways, is also used in protection from oxidative damage by hydrogen peroxide, superoxide and highly reactive oxidant generated during metabolism, the toxicity of the antimalarial drug and toxic ingredient of fava-beans. During detoxification, hydrogen peroxide is converted to water by reduced glutathione and glutathione peroxidase enzyme. Now oxidized glutathione is converted to reduced glutathione by glutathione reductase and NADPH. In glucose 6-P deficient persons, NADPH production is inhibited, so oxidized glutathione not converted into its reduced form, now detoxification of hydrogen peroxide is also inhibited. Hydrogen peroxide also breaks into water and oxygen by the catalase enzyme, which also requires NADPH, so this step is also inhibited. Then hydrogen peroxide can’t be detoxified, so this leads to oxidative damage of cell contents.
Wernicke Korsakoff syndrome (Transketolase and TPP deficiency)
It is caused by a severe deficiency of thiamine (vitamin B1), which is a component of thymine pyrophosphate (TPP). This syndrome is more common in alcoholic persons than nonalcoholic persons. Transketolase transfers two-carbon fragment from ketose to aldose sugar and TPP act as a coenzyme in this process. TPP deficiency leads to inhibition of this reaction. If transketolase is normal (no mutation in the transketolase gene), TPP deficiency is tolerable up to some level and exacerbated by mutation is transketolase. Symptoms include severe memory loss, mental confusion, and partial paralysis.
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