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Chapter 16 Glycogen Metabolism and Gluconeogenesis
Biochemistry/Lab (CHEM 3650)
Nova Southeastern University
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####### Glycogen granules in a liver cell
####### Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy
####### storage in animals and fungi. Glycogen is present in all cells but is most prevalent in
####### skeletal muscle and in liver.
####### The primary structure of glycogen resembles that of amylopectin, but glycogen is more
####### highly branched permitting the rapid mobilization of glucose in times of metabolic need.
####### In the cell, glycogen is degraded for metabolic use by glycogen phosphorylase and
####### glycogen debranching enzyme.
Storage Polysaccharides-Glycogen
Glycogen (in animals, fungi, and bacteria) and starch (in plants) can function to stockpile glucose for later metabolic use. In animals, a constant supply of glucose is essential for tissues such as the brain and red blood cells, which depend almost entirely on glucose as an energy source (other tissues can also oxidize fatty acids for energy; Section 20-2). The mobilization of glucose from glycogen stores, primarily in the liver, provides a constant supply of glucose (~5 mM in blood) to all tissues. When glucose is plentiful, such as immediately after a meal, glycogen synthesis accelerates. Yet the liver's capacity to store glycogen is sufficient to supply the brain with glucose for about half a day. Under fasting conditions, most of the body's glucose needs are met by gluconeogenesis (literally, new glucose synthesis) from noncarbohydrate precursors such as amino acids. Not surprisingly, the regulation of glucose synthesis, storage, mobilization, and catabolism by glycolysis (Section 15-2) or the pentose phosphate pathway (Section 15-6) is elaborate and is sensitive to the immediate and long-term energy needs of the organism. The importance of glycogen for glucose storage is plainly illustrated by the effects of deficiencies of the enzymes that release stored glucose. McArdle's disease, for example, is an inherited condition whose major symptom is painful muscle cramps on exertion. The muscles in afflicted individuals lack the enzyme required for glycogen breakdown to yield glucose glycogen is synthesized normally, it cannot supply fuel for glycolysis to keep up with the demand forATP.
####### Glycogen Breakdown
####### Glycogen granules are especially prominent in the cells that make the greatest use of
####### glycogen: muscle (up to 1–2% glycogen by weight) and liver cells (up to 10% glycogen
####### by weight.
####### Glucose units are mobilized by their sequential removal from the nonreducing ends of
####### glycogen (the ends lacking a C1-OH group). Whereas glycogen has only one reducing end,
####### there is a nonreducing end on every branch. Glycogen's highly branched structure therefore
####### permits rapid glucose mobilization through the simultaneous release of the glucose units at
####### the end of every branch.
####### Glycogen Phosphorylase Degrades Glycogen to Glucose-1-Phosphate
####### Phosphorylase covalently binds the
####### cofactor pyridoxal--5′--phosphate which
####### is a vitamin B 6 derivative. The
####### phosphorylase reaction mechanism which
####### shows how PLP's phosphate group
####### functions as a general acid–base catalyst.
####### Phosphorolysis proceeds along a glycogen branch until it approaches to within 4 or 5
####### residues of an α(1→6) branch point, leaving a “limit branch.” Glycogen debranching
####### enzyme acts as an α(1→4) transglycosylase (glycosyltransferase) by transferring an
####### α(1→4)-linked trisaccharide unit from a limit branch of glycogen to the nonreducing end
####### of another branch.
####### This reaction forms a new α(1→4) linkage with 3 more
####### units available for phosphorylase-catalyzed
####### phosphorolysis. The α(1→6) bond linking the
####### remaining glycosyl residue in the branch to the main
####### chain is hydrolyzed (not phosphorylyzed) by the same
debranching enzyme to yield glucose and debranched
####### glycogen. About 10% of the residues in glycogen (those
####### at the branch points) are therefore converted to glucose
####### rather than G1P. Debranching enzyme has separate
####### active sites for the transferase and the α(1→6)-
####### glucosidase reactions which improves the efficiency of
####### the debranching process.
Glycogen Debranching Enzyme
####### Phosphoglucomutase Interconverts Glucose-1-Phosphate and Glucose-6-Phosphate
The G6P produced by glycogen breakdown can continue along the glycolytic pathway or the pentose phosphate pathway. In the liver, G6P is also made available for use by other tissues. Because G6P cannot pass through the cell membrane, it is first hydrolyzed by glucose-6-phosphatase (G6Pase). G6Pase resides in the endoplasmic reticulum (ER) membrane. Consequently G6P must be imported into the ER by a G6P translocase before it can be hydrolyzed. The resulting glucose and Pi are then returned to the cytosol via specific transport proteins. A defect in any of the components of this G6P hydrolysis system results in type I glycogen storage disease. Glucose leaves the liver cell via a specific glucose transporter named GLUT2 and is carried by the blood to other tissues. Muscle and other tissues lack G6Pase and therefore retain their G6P.
####### Glucose-6-Phosphatase Generates Glucose in the Liver.
UDP–Glucose Pyrophosphorylase Activates Glucosyl Units
####### The reaction catalyzed by UDP–glucose pyrophosphorylase
Glycogen Synthase Extends Glycogen Chains
Glycogenin Primes Glycogen Synthesis. Glycogen synthase cannot simply link together two glucose residues; it can only extend an already existing α(1→4)-linked glucan chain. How, then, is glycogen synthesis initiated? In the first step of this process, a 349-residue protein named glycogenin, acting as a glycosyltransferase, attaches a glucose residue donated by UDPG to the OH group of its Tyr 194. Glycogenin then extends the glucose chain by up to seven additional UDPG-donated glucose residues to form a glycogen “primer.” Only at this point does glycogen synthase commence glycogen synthesis by extending the primer. Analysis of glycogen granules suggests that each glycogen molecule is associated with only one molecule each of glycogenin and glycogen synthase.
Control of Glycogen Metabolism
The opposing processes of glycogen breakdown and
synthesis are reciprocally regulated by allosteric
interactions and the covalent modification of key
enzymes.
Glycogen metabolism is ultimately under the control
of hormones such as insulin, glucagon, and
epinephrine.
####### Glycogen Phosphorylase and Glycogen Synthase Are underAllosteric Control
Both glycogen phosphorylase and glycogen synthase are under allosteric control by effectors that include ATP, G6P, and AMP. Muscle glycogen phosphorylase is activated by AMP and inhibited by ATP and G6P. This suggests that when there is high demand for ATP (low [ATP], low [G6P], and high [AMP]), glycogen phosphorylase is stimulated and glycogen synthase is inhibited, which favors glycogen breakdown. Conversely, when [ATP] and [G6P] are high, glycogen synthesis is favored because glycogen synthase is activated by G6P. Control by allosteric effectors is superimposed on control by covalent modification.
Kinase is a type of enzyme that transfers phosphate groups from high-energy
donor molecules, such as ATP, to specific substrates, a process referred to as
phosphorylation.
Phosphorylas is an enzyme that catalyzes the addition of a phosphate group
from an inorganic phosphate (phosphate+hydrogen) to an acceptor.
Phosphatase is an enzyme that removes a phosphate group from its substrate
by hydrolysing phosphoric acid monoesters into a phosphate ion and a
molecule with a free hydroxyl group
Enzymes for Phosphate Group Transferring
####### Glycogen Phosphorylase Is Activated by Phosphorylation.
####### Phosphorylase Kinase Is Activated by Phosphorylation
####### and by Ca2+. Ca2+ concentrations as low as 10– 7 M
####### activate phosphorylase kinase by inducing a
####### conformational change in the γ subunit which is
####### calmodulin.
####### The physiological significance of the Ca2+ trigger for this activation is that muscle
####### contraction is also triggered by a transient increase in the level of cytosolic Ca2+. The rate
####### of glycogen breakdown is thereby linked to the rate of muscle contraction.
The adenylate cyclase signaling system
####### Turning off the
####### signal
####### transduction
Activation of protein kinaseA
Hormonal Control of Glycogen Metabolism
Chapter 16 Glycogen Metabolism and Gluconeogenesis
Course: Biochemistry/Lab (CHEM 3650)
University: Nova Southeastern University
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