Chapter 13 (part 1) Additional Pathways in Carbohydrate Metabolism.

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 non-reducing 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-6-phosphate 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 tissuesGlucagon• Secreted by pancreas in response to low blood

[glucose]• Stimulates glycogen breakdown• Acts primarily in liverEphinephrine• 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

• 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

PEP Carboxykinase

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