Pentose Phosphate Pathway: Roles, Regulation, and Metabolic Implications

1. Ferchmin 2019 Part of glucose is not metabolized through glycolysis but through “a shunt” involving phosphopentoses • Pentose phosphate pathway or shunt (PPP). 2) Oxidative and isomerization parts. 3) Regulation 4) Metabolic roles of PPP 5) Reduction of glutathione. In glycolysis there was no net oxidation/reduction only “reshuffling” of the redox state of the carbons PENTOSE PHOSPHATE SHUNT or HEXOSE MONOPHOSPHATE PATHWAY This pathway consists of two parts: 1) Glucose-6-P undergoes two oxidations by NADP+, the second is an oxidative decarboxylation that forms a pentose-P. 2) The P-pentoses that are formed during the first part are transformed into glucose-6-P.

2. The phosphoryl group on the 2′-hydroxyl group of one of the ribose units of NADPH distinguishes NADPH from NADH. There is a fundamental distinction between NADPH++H and NADH++H in biochemistry: NADH is oxidized by the respiratory chain to generate ATP, whereas NADPH serves as a reductant in biosynthetic processes.

3. GPDH deficiency is relatively common in persons with roots from regions with endemic malaria. In glycolysis followed by TCA (Kreb’s) cycle the first Cs to be converted to CO2 are # 3 and 4. In PPP is C #1.

4. 2) Nonoxidative steps of pentose phosphate shunt transketolase requires thiamine pyrophosphate (vitamin B1) transketolase requires thiamine pyrophosphate (vitamin B1) Positive regulator of lipid synthesis

5. GSSG is oxidized and GSH is reduced glutathione. To be discussed in a moment.

6. The pentose phosphate pathway (PPP) was explained in the previous slides. The next three slides address the anti-oxidative role of the PPP Glutathione synthesis is not ribosomal and glutathione is not directly encoded in DNA. Notice the unusual bonds between cysteine and glutamate. Unusual “peptide” bond.

8. Sugar nucleotides and glycogen metabolism Several nucleotides can activate sugars. In the case of glucose for glycogen synthesis it is UTP. See next page The first reaction a), is reversible but it is coupled to b) that releases -5 kcal/mol and favors reaction a).

9. Sugar nucleotides of glucose or of any other carbohydrate are called activated because sugars bound to nucleotides can be transferred by specific enzymes to proteins and other molecules or can be subjected to enzymatic modifications possible only with activated sugars. UDP-glucuronic is important for detoxification of many drugs and metabolites. Below is shown the formula of conjugated bilirubin: We, primates, lost the ability to make ascorbate. Therefore we are genetically deficient.

10. Galactose metabolism Fructose is an ketose, therefore it is not a substrate of aldose reductase and causes no cataracts. Glucose and galactose are aldoses and they do cause cataracts • Deficiency of galactokinase causes a mild form of galactosemia (galactose deficiency) that causes cataracts. • Deficiency of hexose-1-phosphate-uridylyl transferase causes the sever type of galactosemia with liver failure, mental retardation and cataracts. • The name galactose-1-phosphate-uridylyl transferase is simply wrong but commonly used. The correct name is hexose-1-phosphate uridylyl transferase. This is so because it transfers equally well glucose as it does galactose. So, the name in the fig is not in agreement with the commission for enzyme nomenclature but it is used in books and in the most exams • The 4 epimerase uses NAD+ as cofactor and the transition state is 4 keto-hexose. • Several mutations of 4 epimerase are known, however, they are rarely expressed and always have residual activity. Why complete loss of activity of 4-epimerase would be lethal?