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Transcript
Storage of glucose (glycogenesis) Glycogen synthesis (glycogenesis) - liver, kidney store glycogen to replenish blood glucose (during food deprivation) for use by brain and RBCs - Muscle stores glycogen for needs of individual cells - glycogen’s highly branched structure excludes water to decrease a tissue osmotic effect and increases its efficiency as a substrate for glycogen phosphorylase, which removes glucose units from the ends of branches - glycogen synthesized from glucose - glucose phosphorylated in glycolysis by glucokinase (liver) or hexokinase (muscle, kidney) glucose-6-P (ATP used) - in muscle and heart produce glycogen from lactate; these tissues have all enzymes for gluconeogenesis except glucose-6-phosphatase (no free glucose produced) - glucose-6-P glucose-1-P by phosphoglucomutase - glucsose-1-P (glucose residue to be added to growing glycogen molecule) is activated chemically by attachment to UMP (derived from UTP) forms UDP-glucose; reaction catalyzed by glucose-1-P uridyltransferase; UTP used, 2 PPi removed UMP, but UDPglucose has 2 phosphates the other one is from the glucose-1-P; highly exergonic - UDP-glucose serves as substrate for glycogen synthase; glycogen synthase regulated by covalent modification (phosphorylation) in response to hormonal signals, and by allosteric activation 1. Mobilization of glucose (glycogenolysis) Glycogen degradation (glycogenolysis) - principal enzyme is glycogen phosphorylase hydrolysis of glucose residues from ends of branches and phosphorylation of these residues - enzyme contains binding sites for its substrates (glycogen, Pi), a cofactor (pyridoxal phosphate), an allosteric activator (AMP), and allosteric inhibitors (ATP, glucose, glucose6-P) -enzyme can be activated by phosphorylation in response to hormonal signals; phosphorylated “a” form and dephosphorylated “b” form - debranching enzyme and transferase move final four residues of branch to the end of a chain so they can be removed by glycogen phosphorylase - Glucose-1-P glucose-6-P by phosphoglucomutase - in liver, glucose-6-P dephosphorylated to glucose via glucose-6-Pase (last enzyme of gluconeogenesis); glucose exported to blood - in liver, glucose-6-P from glycogen, during postabsorptive phase of food deprivation, is not metabolized via glycolysis; pathway inhibited by absence of fructose-2,6-BP inhibition of PFK-1; caused by glucagon FBPase-2 active less fructose-2,6-BP increase FBPase-1 and decrease PFK-1 - muscle lacks glucose-6-Pase cannot synthesize glucose; instead breakdown of glycogen (via glycogen phosphorylase) provides energy by feeding glucose-6-P into glycolysis pyruvate anaerobic LDH lactate or pyruvate Acetyl CoA via PDH CO2 via citric acid cycle 2. Synthesis of glucose (gluconeogenesis) - synthesis of carbohydrate from noncarbohydrate precursors - uses reaction in both mitochondria and cytoplasm - gluconeogenesis occurs largely in liver; kidney makes some contribution during starvation; in kidney glutamine released from muscle is primary gluconeogenic precursor - starvation liver glycogen depleted gluconeogenesis essential for maintaining blood glucose homeostasis - muscle uses pathway for conversion of lactate to glycogen instead of lactate to glucose Pyruvate carboxylase: Pyruvate oxaloacetate (ATP + HCO-3 ADP + Pi, biotin cofactor) - like other carboxylases requires biotin as a prosthetic group to carry CO2, and requires ATP to drive the reaction - direct energy utilization for gluconeogenesis - glucose has 6 carbons so two molecules of ATP used for each molecule of glucose synthesized from pyruvate - reactions only for those precursors that must be converted to glucose via pyruvate (lactate, alanine, other amino acids) Phosphoenolpyruvate carboxykinase- PEPCK: oxaloacetate phosphoenolpyruvate (GTP GDP + HCO-3) - rate-determining and committed step of gluconeogenesis - utilizes GTP as an energy source; 2 molecules of substrate consumed for each molecule of glucose synthesized - any precursors converted to one of citric acid cycle intermediates (oxaloacetate, fumarate, succinyl CoA, alpha-ketoglutarate) use PEPCK as first reaction of gluconeogenesis - PEPCK induced (increase synthesis by DNA transcription) by glucocorticoids (cortisol) during starvation; PEPCK synthesis inhibited by insulin in fed state 3. Biotin - a prosthetic group cofactor for enzymes catalyzing carboxylation reactions - four reactions that require biotin are pyruvate carboxylase, MCC (leucine catabolism), PCC (metabolism of met, ile, val and oxidation of fatty acids), acetyl-CoA carboxylase (ACC) - biotin is covalently attached to a lysine residue on apoenzymes in a reaction catalyzed by holocarboxylase synthetase - when holoenzymes (apoenzymes + biotin) are degraded biocytin (biotin + lysine conjugate) released biotinidase cleaves biocytin to recycle biotin - human requirements for biotin met through synthesis by intestinal bacteria - apparent biotin deficiency caused by genetic defects of carboxylases, holocarboxylase synthetase or most commonly biotinidase 4. Fructose-1,6-BPase (FBPase-1) - forms a futile cycle with PFK-1 - if PFK-1 and FBPase-1 were not reciprocally regulated, ATP would be hydrolyzed by PFK-1 with the phosphatase releasing phosphate rather than replacing the ATP energy lost without conservation - disengaging this regulation occurs naturally and produces heat for the shivering reflex 5. Glucose-6-phosphatase - produces glucose from glucose-6-phosphate (produced from gluconeogenic pathway) - glucose-6-P transported into ER for dephosphorylation; glucose-6-Pase resides in ER - glucose and Pi are returned to the cytoplasm - glucose is exported to the blood and Pi remains in the cell 6. Reactions common to gluconeogenesis and glycolysis - remaining enzymes in gluconeogenesis are reverse reaction of glycolysis; convert two molecules of PEP one molecule of fructose-1,6-BP - one of the two molecules of glyceraldehyde-3-P intermediate must be converted to dihydroxyacetone phosphate - two molecules of ATP (phosphoglycerate kinase) and NADH (glyceraldehyde-3-P dehydrogenase) are required to produce fructose-1,6-BP Metabolism of key gluconeogenic precursors - primary precursors for hepatic glucose production are lactate (40%) and alanine (25%), which are first converted to pyruvate via LDH and alanine aminotransferase - pyruvate carboxylated to oxaloacetate via pyruvate carboxylase - for other amino acids to serve as precursors to glucose, they must be converted to pyruvate or a citric acid cycle intermediate - substance converted to acetyl CoA cannot be a precursor to glucose, because it is consumed in the citric acid cycle and PDH is irreversible Lactate as a precursor - lactate is the primary source of carbons for gluconeogenesis - it is derived from other RBCs or from muscle cells during exercise - lactate glucose pathway includes both pyruvate carboxylase and PEPCK in mitochondrial matrix - PEPCK product PEP transported to cytoplasm for gluconeogenesis completion - need for NADH during reversal of glyceraldehyde-3-P dehydrogenase, but lactate provides this directly in the cytoplasm via lactate dehydrogenase (LDH) Alanine as a precursor - most important amino acid serving as a precursor to glucose - alanine as substrate pyruvate produced via alanine aminotransferase - produced in large amounts in muscle (short-term starvation up to one week) 7. Glycogen storage diseases Type 1: Von Gierke disease; Glucose-6-Pase defect - hypoglycemia due to defect in final step of gluconeogenesis; affects only liver/renal tubule cells - decreased mobilization of glycogen produces hepatomegaly - decreased gluconeogenesis causes accumulation of lactate lactic academia Type V: McArdle disease; skeletal muscle glycogen phosphorylase defect - liver enzyme normal - weakness/cramping of skeletal muscle after exercise - no rise in blood lactate during strenuous exercise - muscle contains a high level of glycogen with normal structure Type VI: Hers disease; liver glycogen phosphorylase defect - marked hepatomegaly due to a high level of glycogen with normal structure - glucagon administration no increase in blood glucose