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Transcript
Pentose phosphate pathway = PPP 5 C containing phosphorylated sugar is produced Pentose phosphate cycle 5 C containing phosphorylated sugar is produced the pathway can work as a cycle Glucose direct oxidation alternative route for glucose oxidation besides glycolysis in cytoplasm Hexose monophosphate shunt alternative metabolism for a 6 C containing sugar Pentose phosphate pathway has two phases/branches: 1.) oxidative, irreversible, non-equilibrium, regulated, anaerob, 2.) nonoxidative, reversible, near-equilibrium, non-regulated, anaerob, Characteristics of PPP: each intermediate bears one phosphate at the terminal position intermediates are 3-7 C-atom containing sugars and 6 C-atom cont. sugaracid: aldonic acid Significance of PPP 1.) NADPH production in the oxidative phase for reductive synthetic reactions, for biotransformation 2.) ribose-5-phosphate is produced after the oxidative branch in the nonoxidative branch or if only the nonoxidative branch works from the end for nucleotide synthesis Oxidative, irreversible, regulated phase of PPP The whole pathway is in the cytoplasm. reversible steps in 3 steps Comparison of transketolase and transaldolase transketolase transaldolase thiamin pyrophosphate prosthetic group no coenzyme 2 carbon cantaining keto group is transfered from ketose to aldose 3 C containing keto group is transfered from ketose to aldose carbanions are resonance stabilized If oxidative branch is absent e.g. muscle or if NADPH requirement << ribose-5P need gluconeogenesis glycolysis nonoxid. PPP If NADPH and ribose-5P need are balanced e.g. in liver oxidative PPP whole PPP If only NADPH is necessary e.g. in adipose t. whole PPP glycolysis If NADPH and ATP needs e.g. in liver Localization of PPP oxidative branch = where NADPH is necessary 1.) The whole pathway is found in the cytoplasm where lipid synthesis or biotransformation is significant ¾FA synthesis: liver, adipose tissue, lactating mammary gland, brain ¾cholesterol synthesis: liver, skin, gut, brain ¾bile acid synthesis: liver ¾steroid hormon synth.: adrenal cortex, ovary, testis, adipocytes, brain ¾biotransformation: liver, lung, kidney, gut, blood cells Regulation of pentose phosphate pathway oxidative phase and the whole pathway 1.) NADPH, the coenzyme product of the dehydrogenases inhibits the dehydrogenases, no need for the PPP, if NADPH is not consumed in other reactions 2.) NADP, the substrate coenzyme activates the dehydrogenases, it is produced by other reactions 3.) insulin in well fed state induces the PPP dehydrogenases to have NADPH for the fatty acid (and further TAG) synthesis in adipocytes 4.) some molecules that induce reactions of biotransformation, induce PPP dehydrogenase enzymes as well, to produce NADPH for biotransformation Localization, speed and significance of nonoxidative branch of PPP The nonoxidative reversible pathway is found in every cells having nucleus, it goes from the end backword to produce ribose-5P for nucleotide/nucleic acid synthesis (ribose-5P concentration of blood is low, even its absorption is negligable, but possible across GLUT) Nonoxidative reversible reactions take place to that direction and speed, that is determined by the substrate/product ratio, overall the building of ribose-5P to nucleotides. From fructose-6P and glyceraldehyde-3P the ribose-5P is produced, from the end in the reverse direction e.g. in muscle. The role of nucleotides: ATP, GTP, CTP, UTP are energy donating compound in coupled reaction, they have regulatory role in enzyme reaction, transporters cAMP, cGMP are second messengers during signal transduction of neurotransmitters, hormons, paracrin hormons nucleic acids: RNA, DNA are synthesized from them for the synthesis of nucleotide type coenzymes: NAD, NADP, FAD, FMN, SAM, CoA Importance of PPP in red blood cells glu-6P or 6P-gluconate NADP 2 GSH H2O2 GSSG 2 H2O O2 dehydrogenases NADPH pentosephosphate path. glutathione reductase glutathione peroxidase H2O2 reacts with iron ion to form reactive oxygen species = ROS, that react with unsaturated fatty acids in phospholipid membranes. This is the lipid peroxidation. Fatty acids are broken, membrane becomes leaky, red blood cells are hemolysed. If in the patient the glucose-6-P-dehydrogenase activity is decreased because of mutation and the patient takes medicines (acetyl-salycilate, primaquin, sulfonamides, etc.) that react with GSH, so GSH is not enough for reduction of hydrogen-peroxide, rbc. are hemolyzed. Before uroic acid pathway: glucose from blood ↓hexokinases glu-6P phosphoglucomutase epimerase UDP-gal glu-1P gal-1P-uridyl transferase UDP-glu gal-1P galactokinase gal from blood (from lactose e.g.) stored glycogen ↓ glu-1P UTP glu-1P uridyltransferase PP UDP-glu Uronic acid pathway UDP-glucuronate is needed for conjugation reactions in biotransformation and synthesis of heteropolysaccharides branchpoint to ascorbate synthesis: not in humans continuation of PPP: vitamin: not produced in humans : interconnection in carbohydrate metabolism glycolysis gluconeogenesis fructose degradation pentosephosphate path. glycogen metabolism lactose/galactose met. uronic acid pathway aminosugar synth. glycoprotein synth. proteoglycan synt.