Transcript Chapter 13 (part 1) - University of Nevada, Reno

Chapter 13 (part 1)
Additional Pathways in
Carbohydrate Metabolism
Metabolism of Tissue Glycogen
• But tissue glycogen is an important energy reservoir
- its breakdown is carefully controlled
• Glycogen consists of "granules" of high MW
• Glycogen phosphorylase cleaves glucose from the
nonreducing ends of glycogen molecules
• This is a phosphorolysis, not a hydrolysis
• Metabolic advantage: product is a sugar-P - a
"sort-of" glycolysis substrate
•Glycogen phosphorylase
cleaves glycogen at nonreducing end to generate
glucose-1-phosphate
•Debranching of limit dextran
occurs in two steps.
•1st, 3 X 1,4 linked glucose
residues are transferred to
non-reducing end of glycogen
•2nd, amylo-1,6-glucosidase
cleaves 1,6 linked glucose
residue.
•Glucose-1-phosphate is
converted to glucose-6phosphate by
phosphoglucomutase
Glycogen Synthase
• Forms -(1 4) glycosidic bonds in glycogen
• Glycogen synthesis depends on sugar nucleotides
UDP-Glucose
• Glycogenin (a protein!) protein scaffold on which
glycogen molecule is built.
• Glycogen Synthase requires 4 to 8 glucose primer on
Glycogenin (glycogenein catalyzes primer formation)
• First glucose is linked to a tyrosine -OH
• Glycogen synthase transfers glucosyl units from
UDP-glucose to C-4 hydroxyl at a nonreducing end
of a glycogen strand.
Control of Glycogen Metabolism
• A highly regulated process, involving reciprocal
control of glycogen phosphorylase (GP) and
glycogen synthase (GS)
• GP allosterically activated by AMP and inhibited
by ATP, glucose-6-P and caffeine
• GS is stimulated by glucose-6-P
• Both enzymes are regulated by covalent
modification - phosphorylation
Hormonal Regulation of Glycogen Metabolism
Insulin
• Secreted by pancreas under high blood [glucose]
• Stimulates Glycogen synthesis in liver
• Increases glucose transport into muscles and adipose
tissues
Glucagon
• Secreted by pancreas in response to low blood
[glucose]
• Stimulates glycogen breakdown
• Acts primarily in liver
Ephinephrine
• Secrete by adrenal gland (“fight or flight” response)
• Stimulates glycogen breakdown.
• Increases rates of glycolysis in muscles and release of
glucose from the liver
Hormonal Regulation of Glycogen
Metabolism
Effect of glucagon and epinephrine on glycogen
phosphorylase glycogen synthase activities
Effect of insulin on glycogen phosphorylase
glycogen synthase activities
Gluconeogenesis
• Synthesis of "new glucose" from common
metabolites
• Humans consume 160 g of glucose per day
• 75% of that is in the brain
• Body fluids contain only 20 g of glucose
• Glycogen stores yield 180-200 g of glucose
• The body must still be able to make its own
glucose
Gluconeogenesis
• Occurs mainly in liver and kidneys
• Not the mere reversal of glycolysis
for 2 reasons:
– Energetics must change to make
gluconeogenesis favorable (delta G of
glycolysis = -74 kJ/mol
– Reciprocal regulation must turn one on
and the other off - this requires
something new!
• Seven steps of glycolysis
are retained
• Three steps are replaced
• The new reactions
provide for a
spontaneous pathway (G
negative in the direction
of sugar synthesis), and
they provide new
mechanisms of regulation
Pyruvate Carboxylase
• The reaction requires ATP and bicarbonate as
substrates
• Biotin cofactor
• Acetyl-CoA is an allosteric activator
• Regulation: when ATP or acetyl-CoA are high,
pyruvate enters gluconeogenesis
PEP Carboxykinase
• Lots of energy needed to drive this reaction!
• Energy is provided in 2 ways:
– Decarboxylation is a favorable reaction
– GTP is hydrolyzed
• GTP used here is equivalent to an ATP
PEP Carboxykinase
• Not an allosteric enzyme
• Rxn reversible in vitro but irreversible in
vivo
• Activity is mainly regulated by control of
enzyme levels by modulation of gene
expression
• Glucagon induces increased PEP
carboxykinase gene expression
Fructose-1,6-bisphosphatase
• Thermodynamically favorable - G
in liver is -8.6 kJ/mol
• Allosteric regulation:
– citrate stimulates
– fructose-2,6--bisphosphate inhibits
– AMP inhibits
Glucose-6-Phosphatase
• Presence of G-6-Pase in ER of liver and kidney cells
makes gluconeogenesis possible
• Muscle and brain do not do gluconeogenesis
• G-6-P is hydrolyzed as it passes into the ER
• ER vesicles filled with glucose diffuse to the plasma
membrane, fuse with it and open, releasing glucose
into the bloodstream.
•Metabolites other than
pyruvate can enter
gluconeogenesis
•Lactate (Cori Cycle)
transported to liver for
gluconeogenesis
•Glycerol from
Triacylglycerol catabolism
•Pyruvate and OAA from
amino acids
(transamination rxns)
•Malate from glycoxylate
cycle -> OAA ->
gluconeogenesis
Regulation of Gluconeogenesis
• Reciprocal control with glycolysis
• When glycolysis is turned on, gluconeogenesis
should be turned off
• When energy status of cell is high, glycolysis
should be off and pyruvate, etc., should be
used for synthesis and storage of glucose
• When energy status is low, glucose should be
rapidly degraded to provide energy
• The regulated steps of glycolysis are the
very steps that are regulated in the reverse
direction!
Pentose Phosphate Pathway
• Provides NADPH for biosynthesis
• Produces ribose-5-P for RNA and DNA
• oxidative steps (formation of NADPH)
followed by non-oxidative steps
• Cytosolic pathway
• Active in tissues that synthesis fatty acids
and sterols (liver, mammary glands, adrenal
glands, adipose tissue)
• Active in red blood cells to maintain heme in
reduced form.
Oxidative Stage
Non-oxidative
Stage