--- module: 088-03 language: en chapter: 88 title: "Carbohydrate Metabolism, Bioenergetics, and Mitochondrial Integration" module_title: "Glycogen, pentose-phosphate pathway, NADPH, and integrated carbohydrate control" source_sha256: 11b77b1f5292f83c89ab88dca7a5516e0a8cf596ed348139ad08fb949fe2105a --- # Glycogen, pentose phosphate, NADPH, integration ## Glycogen structure and synthesis ### Alpha 1-4 chains with alpha 1-6 branches ### Glycogenin primes synthesis ### Branches create many nonreducing ends #### Simultaneous synthesis or breakdown #### Greater solubility ### Liver buffers blood, muscle fuels contraction ### Phosphoglucomutase makes glucose 1-phosphate ### UTP activates to UDP-glucose ### Glycogen synthase adds alpha 1-4 links ### Branching enzyme creates alpha 1-6 links ## Glycogen breakdown ### Phosphorylase uses inorganic phosphate #### Conserves energy versus hydrolysis ### Stops near branches #### Debranching enzyme transfers, then hydrolyses #### Small amount of free glucose ### Liver glucose-6-phosphatase exports glucose ### Muscle lacks it, feeds glycolysis ### Stored with water, depletion shifts mass ## Hormonal and allosteric control ### Synthase active when dephosphorylated #### Glucose six-phosphate stimulates #### Insulin activates phosphatases ### Glucagon acts on liver, not muscle #### cAMP and PKA activate phosphorylase #### Synthase inhibited ### Epinephrine acts on liver and muscle ### Contraction calcium via calmodulin #### Activates phosphorylase kinase ### Muscle phosphorylase: AMP on, ATP off ### Liver phosphorylase responds to glucose ### Reciprocal phosphorylation limits cycling ## Glycogen-storage disorders ### Hepatic: fasting hypoglycaemia, hepatomegaly ### Lysosomal: cardiomyopathy, myopathy ### Muscle: exercise intolerance, cramps #### Rhabdomyolysis ### Abnormal branching: insoluble polymer ## Pentose-phosphate pathway ### Cytosolic, oxidative and nonoxidative phases ### Oxidative phase starts with G6PD #### Two NADPH, CO2, ribulose 5-phosphate #### Irreversible, driven by NADP plus ### Nonoxidative phase interconverts sugars #### Transketolase moves two carbons, needs TPP #### Transaldolase moves three carbons #### Ribose 5-phosphate for nucleotides ### Adapts to NADPH versus ribose need #### NADPH need: recycle pentoses, lose CO2 ## NADPH roles and deficiencies ### Glutathione, lipid synthesis, P450, NO ### Distinct from energy-carrying NADH ### Erythrocytes rely on it for glutathione #### G6PD deficiency: episodic haemolysis #### Infection, drugs, oxidant foods trigger #### X-linked, variable severity ### Phagocyte NADPH oxidase makes superoxide #### Defect: chronic granulomatous disease ### Glucuronic acid for conjugation #### Humans cannot make vitamin C ## Fed, fasting, and exercise states ### Fed liver: glycogen, NADPH, fatty acids ### Adipose makes glycerol-3-phosphate ### Early fasting: hepatic glycogenolysis ### Later: gluconeogenesis, kidney rises #### Brain shifts to ketone bodies #### Erythrocytes remain glycolytic ### Exercise: insulin-independent uptake ### After exercise: glycogen replenished ## Hyperglycaemic injury ### Insufficient insulin raises harmful flux ### Polyol pathway makes sorbitol with NADPH #### Osmotic and redox stress #### Lens, nerve, retina, kidney ### Advanced glycation cross-links proteins #### Stiffens matrix, triggers inflammation ### Glycated haemoglobin tracks exposure #### Distorted by red-cell turnover, variants ## Timescales and interpretation ### Allosteric immediate, phosphorylation minutes ### Transcription over hours to days ### Snapshot reflects several histories ### Concentration differs from flux ### Disease when a branch cannot respond