GLYCOLYSISGLUCONEOGENESIS-74-86.pdf

Pentose Phosphate Pathway Major source for the NADPH required for anabolic processes (parallel to glycolysis). Gluconeogenesis is directly connected to the pentose phosphate pathway. As the need for glucose-6-phosphate (the beginning metabolite in the pentose phosphate pathway) i...

Pentose Phosphate Pathway Major source for the NADPH required for anabolic processes (parallel to glycolysis). Gluconeogenesis is directly connected to the pentose phosphate pathway. As the need for glucose-6-phosphate (the beginning metabolite in the pentose phosphate pathway) increases so does the activity of gluconeogenesis. w Other names: Phosphogluconate Pathway Hexose Monophosphate Shunt w The linear part of the pathway carries out oxidation and decarboxylation of the 6-C sugar glucose-6-P, producing the 5-C sugar ribulose-5-P. w Production of ribose-5-P is precursor for nucleotide synthesis.  Glucose-6-phosphate 6-Phospho- O O- Dehydrogenase glucono- 1C 6CH2OPO32- 6 CH OPO 2- lactonase + 2 3 NADPH + H HC OH H 5 O OH NADP + H 5 O H2O H+ 2 H H HO 3CH 4 OH H 1 4 OH H O 1 HC OH 4 OH H OH 3 2 3 2 HC OH 5 H OH H OH CH2OPO32- 6 glucose-6-phosphate 6-phospho-glucono-lactone 6-phospho-gluconate Glucose-6-phosphate Dehydrogenase catalyzes oxidation of the aldehyde (hemiacetal), at C1 of glucose-6-phosphate, to a carboxylic acid, in ester linkage (lactone). NADP+ serves as electron acceptor.  Glucose-6-phosphate 6-Phospho- O O- Dehydrogenase glucono-lactonase 1C 6CH2OPO32- 6 CH OPO 2- + 2 3 NADPH + H HC OH H 5 O OH NADP + H 5 O H2O H+ 2 H H HO 3CH 4 OH H 1 4 OH H O 1 HC OH 4 OH H OH 3 2 3 2 HC OH 5 H OH H OH CH2OPO32- 6 glucose-6-phosphate 6-phospho-glucono-lactone 6-phospho-gluconate 6-Phospho-glucono-lactonase catalyzes hydrolysis of the ester linkage, resulting in ring opening. The product is 6-phospho-gluconate. Although ring opening occurs in the absence of a catalyst, 6-Phospho-glucono-lactonase speeds up the reaction, decreasing the lifetime of the highly reactive, and thus potentially toxic, 6-phospho-glucono=lactone.  O O- Phosphogluconate 1C Dehydrogenase HC OH 1CH2OH 2 NADP+ NADPH + H+ HO 3CH C O 2 HC OH HC OH 4 3 HC OH CO2 HC OH 5 4 CH2OPO32- CH2OPO32- 6 5 6-phospho-gluconate ribulose-5-phosphate Phospho-gluconate Dehydrogenase catalyzes oxidative decarboxylation of 6-phosphogluconate, to yield the 5- C ketose ribulose-5-phosphate. The OH at C3 (C2 of product) is oxidized to a ketone. This promotes loss of the carboxyl at C1 as CO2. NADP+ serves as oxidant. Reduction of NADP+ (as with NAD+) involves transfer of 2 e- and 1 H+ to the nicotinamide moiety. w NADPH, a product of the Pentose Phosphate Pathway, functions as a reductant in anabolic (synthetic) pathways, e.g., fatty acid synthesis. w NAD+ serves as electron acceptor in catabolic pathways, in which metabolites are oxidized. The resultant NADH is reoxidized by the respiratory chain, producing ATP. Regulation of Glucose-6-phosphate Dehydrogenase: w Glucose-6-phosphate Dehydrogenase is the committed step of the Pentose Phosphate Pathway. This enzyme is regulated by availability of the substrate NADP+. w As NADPH is utilized in reductive synthetic pathways, the increasing concentration of NADP+ stimulates the Pentose Phosphate Pathway, to replenish NADPH. The rest of the pathway converts ribulose-5-P to the 5-C product ribose-5-P, or to 3-C glyceraldehyde-3-P & 6-C fructose-6-P. Additional enzymes include an Isomerase, Epimerase, Transketolase, and Transaldolase. The overall (3) ribulose-5-P mechanism if we IS EP start with 3 molecules of R-5-P: ribose-5-P (2) xylulose-5-P The diagram at right TK summarizes flow of 15 C atoms through glyceraldehyde-3-P Pentose Phosphate Pathway reactions sedoheptulose 7 P by which 5-C sugars are converted to 3-C and 6-C sugars. fructose-6- P TA IS = Isomerase EP = Epimerase erythrose-4-P TK = Transketolase TA = Transaldolase TK fructose-6-P glyceraldehyde-3-P The balance sheet below summarizes flow of 15 C atoms through Pentose Phosphate Pathway reactions by which 5-C sugars are converted to 3-C and 6-C sugars. C5 + C5 à C3 + C7 (Transketolase) C3 + C7 à C6 + C4 (Transaldolase) C5 + C4 à C6 + C3 (Transketolase) ____________________________ 3 C5 à 2 C6 + C3 (Overall) Glucose-6-phosphate may be regenerated from either the 3-C glyceraldehyde-3-phosphate or the 6-C fructose-6- phosphate, via enzymes of Gluconeogenesis. Depending on needs of a cell for ribose-5-phosphate, NADPH, and ATP, the Pentose Phosphate Pathway can operate in various modes, to maximize different products. There are three major scenarios: 2 NADP+ 2 NADPH + CO2 glucose-6-P ribulose-5-P ribose-5-P 1 Pentose Phosphate Pathway producing NADPH and ribose-5-phosphate Ribulose-5-P may be converted to ribose-5-phosphate, a substrate for synthesis of nucleotides and nucleic acids. The pathway also produces some NADPH.  2 NADP+ 2 NADPH + CO2 glucose-6-P ribulose-5-P ribose-5-P 2 fructose-6-P, & glyceraldehyde-3-P Pentose Phosphate Pathway producing maximum NADPH Glyceraldehyde-3-P and fructose-6-P may be converted to glucose-6-P for re-entry to the linear portion of the Pentose Phosphate Pathway, maximizing formation of NADPH.  2 NADP+ 2 NADPH + CO2 glucose-6-P ribulose-5-P ribose-5-P 3 fructose-6-P, & glyceraldehyde-3-P to Glycolysis for production of ATP Pentose Phosphate Pathway producing NADPH and ATP Glyceraldehyde-3-P and fructose-6-P, formed from 5-C sugar phosphates, may enter Glycolysis for ATP synthesis. The pathway also produces some NADPH.  2 NADP+ 2 NADPH + CO2 glucose-6-P ribulose-5-P ribose-5-P 3 fructose-6-P, & glyceraldehyde-3-P to Glycolysis for production of ATP Pentose Phosphate Pathway producing NADPH and ATP Ribose-1-phosphate generated during catabolism of nucleosides also enters Glycolysis in this way, after first being converted to ribose-5-phosphate. Thus the Pentose Phosphate Pathway serves as an entry into Glycolysis for both 5-carbon & 6-carbon sugars.