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Carbohydrate Metabolism
Chapter 8
Metabolism Section 8.1: Glycolysis Section 8.2: Gluconeogenesis Section 8.3: The Pentose Phosphate Pathway Section 8.4: Metabolism of Other Important
Sugars Section 8.5: Glycogen Metabolism
Carbohydrate Metabolism
Overview
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
Metabolism and Jet Engines Carbohydrate Metabolism: Biochemical processes
responsible for the formation, breakdown and interconversion of carbohydrates in living organisms
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
Energy transforming pathways of carbohydrate metabolism include: glycolysis,
Glycogenesis Glycogenolysis Gluconeogenesis pentose phosphate
pathway
Section 8.1: Glycolysis
Glycolysis occurs in almost every living cell Ancient process central to all life
Splits glucose into two three-carbon pyruvate unitsCatabolic process that captures some energy as 2 ATP and 2 NADH
Figure 8.2 Major Pathways in Carbohydrate Metabolism
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
ATP
Adenosine triphosphate (ATP) is a nucleoside triphosphate used in cells as a coenzyme to store and transport chemical energy
NAD+/NADH
Nicotinamide adenine dinucleotide (NAD) is a coenzyme found in all living cells that transfers electrons between reactions in metabolism.
Nicotinamide adenine dinucleotide phosphate
• NADPH is the reduced form of NADP+. • NADP+ differs from NAD+ in the presence of an additional phosphate group on
the 2' position of the ribose ring that carries the adenine moiety.• NADPH is a cofactor used in anabolic reactions, such as lipid and nucleic acid
synthesis, which require NADPH as a reducing agent.
Glycolysis is an anaerobic process
Pyruvate
The conjugate base of pyruvic acid
It is a key intermediate in several metabolic pathways
Made from glucose through glycolysis
Converted back to carbohydrates (such as glucose) via gluconeogenesis, or to fatty acids through acetyl-CoA.
Used to construct the amino acid alanine, and be converted into ethanol or lactic acid via fermentation.
Pyruvic Acid
Alanine
Section 8.1: Glycolysis
The Fates of Pyruvate Under aerobic conditions, pyruvate is converted
to acetyl-CoA for use in the citric acid cycle and electron transport chain
Figure 8.7 The Fates of Pyruvate
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
Section 8.1: Glycolysis
The Fates of Pyruvate Under anaerobic conditions pyruvate can
undergo fermentation: alcoholic or homolactic
Figure 8.7 The Fates of Pyruvate
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
Section 8.1: Glycolysis
Energetics of Glycolysis In red blood cells, only three reactions have significantly negative DG values
Many reactions are reversible
Figure 8.9 Free Energy Changes during Glycolysis in Red Blood Cells
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
Section 8.1: Glycolysis
Regulation of Glycolysis The rate of the glycolytic pathway in a cell is
controlled by the allosteric enzymes: Hexokinases I, II, and III Phosphofructokinase 1 (PFK-1) Pyruvate kinase
Reactions catalyzed by these allosteric enzymes can be turned on or off by activator or inhibitor molecules
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
Section 8.1: Glycolysis
Regulation of Glycolysis Continued Pyruvate kinase (converts PEP to pyruvate)
activated by high AMP concentrations, inhibited ATP
PFK-1 is activated by fructose-2,6-bisphosphate, produced via hormone- induced covalent modification of PFK-2
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
Section 8.1: Glycolysis
The peptide hormones glucagon and insulin also regulate glycolysis/gluconeogenesis pathways• Glucagon is released by pancreatic alpha-cells when blood glucose is low;
triggers a series of reactions that inhibit glycolysis and activate gluconeogenesis• Insulin is released by pancreatic beta-cells when blood glucose is high; triggers
a series of reactions that activate glycolysis and inhibit gluconeogenesis
Section 8.2: Gluconeogenesis
Gluconeogenesis is the formation of new glucose molecules from precursors in the liverOccurs when blood sugar levels are low and liver glycogen is depleted
Precursor molecules include lactate, pyruvate, and a-keto acids
Gluconeogenesis Reactions Reverse of glycolysis except the three
irreversible reactions
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
1
2
3 Gluconeogenesis Reactions
Three bypass reactions:1. Synthesis of phosphoenolpyruvate (PEP) via the enzymes pyruvate carboxylase and pyruvate carboxykinase2. Conversion of fructose-1,6-bisphosphate to fructose-6-phosphate via the enzyme fructose-1,6-bisphosphatase3. Formation of glucose from glucose-6-phosphate via the liver and kidney-specific enzyme glucose-6-phosphatase
Section 8.2: Gluconeogenesis
Gluconeogenesis Regulation Rate of gluconeogenesis is affected primarily by: substrate availability allosteric effectors Hormones (e.g., cortisol and insulin)
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
Section 8.2: Gluconeogenesis
Gluconeogenesis Substrates Three of the most important substrates for gluconeogenesis are:
1. Lactate—released by skeletal muscle following exercise After transfer to the liver lactate is converted to pyruvate, then to glucose
2. Glycerol—a product of fat metabolism. Must be converted to their intermediate glyceraldehyde 3-phosphate to produce glucose.
3. Alanine—generated from pyruvate in exercising muscle Alanine is converted to pyruvate and then glucose in the liver
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
Cori Cycle: Lactate produced by anaerobic glycolysis in the muscles moves to the liver and is converted to glucose, which then returns to the muscles and is metabolized back to lactate.
Allosteric Regulation
allosteric effectors may activate (+) or inhibit (-) steps along the metabolic pathways
GLY
CO
LYS
IS
GL
UC
ON
EO
GE
NE
SIS
Hormonal Regulation
The peptide hormones glucagon and insulin also regulate glycolysis/gluconeogenesis pathways• Glucagon is released by pancreatic alpha-cells when blood glucose is low;
triggers a series of reactions that inhibit glycolysis and activate gluconeogenesis• Insulin is released by pancreatic beta-cells when blood glucose is high; triggers
a series of reactions that activate glycolysis and inhibit gluconeogenesis
Alternate glucose metabolic pathway Products are NADPH and ribose-5-phosphate Two phases: oxidative and nonoxidative
Pentose Phosphate Pathway
Section 8.3: Pentose Phosphate Pathway Pentose Phosphate Pathway
Alternate glucose metabolic pathway Most active in cells where large quantities of lipids
are synthesized (e.g., adipose tissue, adrenal cortex, mammary glands, liver)
Two phases: oxidative and nonoxidative Oxidative phase:
Produces ribulose-5-phosphate and two NADPH (Nicotinamide adenine dinucleotide phosphate)
NADPH is a reducing agent used in anabolic (synthesis) processes (e.g., to produce lipids)
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
Pentose Phosphate Pathway – Oxidative Phase
Figure 8.15a The Pentose Phosphate Pathway (oxidative)
Glucose-6-phosphate dehydrogenase
Gluconolactonase
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
Oxidation
Hydrolysis
Figure 8.15a The Pentose Phosphate Pathway (oxidative)
Section 8.3: Pentose Phosphate Pathway
6-phosphogluconate dehydrogenase
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
Oxidation
Decarboxylation
Pentose Phosphate Pathway: Nonoxidative Produces important
intermediates for nucleotide biosynthesis and glycolysis
Ribose-5-phosphate Glyceraldehyde-3-
phosphate Fructose-6-phosphate
Figure 8.15b The Pentose Phosphate Pathway (nonoxidative)
Section 8.3: Pentose Phosphate Pathway
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
Pentose Phosphate Pathway If the cell requires
more NADPH than ribose molecules, products of the nonoxidative phase can be shuttled into glycolysis
Figure 8.16 Carbohydrate Metabolism: Glycolysis and the Phosphate Pathway
Section 8.3: Pentose Phosphate Pathway
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
Section 8.4: Metabolism of Other Important Sugars
Fructose, mannose, and galactose also important sugars for vertebrates Most common sugars found in oligosaccharides besides glucose
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
70%
22%
Section 8.4: Metabolism of Other Important Sugars
Fructose Metabolism Second to glucose in the human diet Found in fruit, honey, sucrose, high fructose
corn syrup Can enter the glycolytic pathway in two ways:
Through the liver (multi-enzymatic process) Muscle and adipose tissue (hexokinase)
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
Section 8.4: Metabolism of Other Important Sugars
Figure 8.17 Carbohydrate Metabolism: Other Important Sugars
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
Glycogenesis Synthesis of glycogen, the storage form of glucose, occurs after a
meal Requires a set of three reactions (1 and 2 are preparatory and 3 is
for chain elongation):1. Synthesis of glucose-1-phosphate (G1P) from glucose-6-phosphate by phosphoglucomutase2. Synthesis of uridine diphosphate (UDP)-glucose from G1P by UDP-glucose phosphorylase3. Synthesis of Glycogen from UDP-glucose
Requires two enzymes: Glycogen synthase to grow the chain Amylo-α(1,46)-glucosyl transferase which creates the
α(1,6) linkages for branching
Section 8.5: Glycogen Metabolism
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
Glycogenesis ContinuedGlycogen synthase catalyzes addition of glucose onto existing oligosaccharide by transferring glucosyl group of UDP-glucose to non-reducing end of glycogen
Figure 8.18 Glycogen Synthesis
Section 8.5: Glycogen Metabolism
Glycogen synthase
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
Branching enzyme
Section 8.5: Glycogen Metabolism
Glycogenesis Continued Branching enzyme
amylo-a(1,41,6)-glucosyl transferase creates a(1,6) linkages for branches that occur ~10 residues apart
Figure 8.18 Glycogen Synthesis
a(1,6) Glycosidic Linkage is formed
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
Glycogenolysis Glycogen degradation requires two reactions:
1. Removal of glucose from nonreducing ends (glycogen phosphorylase), which stops when four glucose units remain at the branch point (further degradation to the branch point results in a limit dextrin)
2. 2. Hydrolysis of the a(1,6) glycosidic bonds at branch points by amylo-a(1,6)-glucosidase (debranching enzyme)
Section 8.5: Glycogen Metabolism
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
Section 8.5: Glycogen Metabolism
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
Glycogen phosphorylase uses organic phophate to cleave the a(1,4) linkages on the outer branches
Section 8.5: Glycogen Metabolism
Glycogenolysis Cont.
amylo-a(1,6)-glucosidase first transfers the outer 3 glucose residues to a nearby non-reducing end, then uses water to hydrolyze the a(1,6) glycosidic bonds and remove the last glucose at the branch point
Amylo-a(1,6)-glucosidase
Amylo-a(1,6)-glucosidase
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
Section 8.5: Glycogen Metabolism
Amylo-a(1,6)-glucosidase
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
Glucose-1-phosphate, the major product of glycogenolysis, is diverted to glycolysis in muscle cells to generate energy for muscle contraction.In hepatocytes, G1P is converted to glucose and released into the blood.
Regulation of Glycogen Metabolism Carefully regulated
by synthesis to maintain consistent energy levels
Regulation involves insulin, glucagon, epinephrine, and allosteric effectors
Section 8.5: Glycogen Metabolism
Figure 8.22 Major Factors Affecting Glycogen Metabolism
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
Figure 8.22 Major Factors Affecting Glycogen Metabolism
Section 8.5: Glycogen Metabolism
Glucagon activates glycogenolysis
Insulin inhibits glycogenolysis and activates glycogenesis
Epinephrine release activates glycogenolysis and inhibits glycogenesis
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
Regulation of Glycogen Metabolism
Glucagon is released from pancreas when blood glucose levels drop (e.g., after a meal). It binds to hepatocyte receptors, triggering a cascade of reactions that initiate glycogenolysis, releasing glucose into the bloodstream.
Insulin inhibits enzymes of glycogenolysis, and activates glycogenesis enzymes, increasing rate of glucose uptake.
Epinephrine, released due to emotional or physical stress, promotes glycogenolysis and inhibits glycogenesis; provides massive glucose release for flight-or-fight response.