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Chapter 8
Metabolism and Jet Engines Section 8.1: Section 8.1: Glycolysis Section 8.2: Section 8.2: Gluconeogenesis Section 8.3: Section 8.3: The Pentose Phosphate Pathway Section 8.4:Section 8.4: Metabolism of Other Important
Energy transforming pathways of carbohydrate metabolism include glycolysis, glycogenesis, glycogenolysis, gluconeogenesis, and pentose phosphate pathway
Figure 8.2 Major Pathways in Carbohydrate Metabolism
The nucleophilic attack of the C6—OH group of glucose on the phosphate of an Mg2+–ATP complex.
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The phosphoryl-transfer reaction catalyzed by hexokinase.
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Conformation changes in yeast hexokinase on binding glucose. (a) Space-filling model of a subunit of free hexokinase. (b) Space-filling model of a subunit of free hexokinase in complex with glucose (purple).
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This same change in conformation
is observed for ALL kinases!
It also accounts for the fact that water cannot be
used for hydrolysis of ATP unless we fool the enzyme
by using xylose instead of glc.
Phosphoglucose isomerase (PGI)
pKs for active site: 6.7 and 9.3(determined by rate vs. pH)
Which aa’s??
Actually Glu (!!!) and His with stabilization of His+ by a Glu (remember the ser protease mechanism!)
Works exactly like HK.
Activated by [AMP] even in the presence of hi [ATP].
Inhibited by hi [ATP]or citrate
Section 8.1: Glycolysis
Reactions of the Reactions of the Glycolytic Pathway Glycolytic Pathway ContinuedContinued
3. Phosphorylation of fructose-6-phosphate
This step is irreversible due to a large decrease in free energy and commits the molecule to glycolysis
4. Cleavage of fructose-1,6-bisphosphate
Aldol cleavage giving an aldose and ketose product
Some reactions employed in elucidating the enzymatic mechanism of GAPDH. (a) The reaction of iodoacetate with an active site Cys residue. (b) Quantitative tritium transfer from substrate to NAD+.
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32Pi also incorporated
Section 8.1: Glycolysis
Oxidation of glyceraldehyde-3-phosphate (G-3-P) is a 2-step process (reaction 6)
G-3-P undergoes oxidation and phosphorylationG-3-P interacts with the sulfhydryl group in the enzyme’s active site
The product’s composition, 3-phosphoglycerateFrom 3 to 2 position can readily mutate
And now 2 phosphoglycerage does something rather strange—Electrons on C@ and 3 proceed to rearrange.
Thus, redox-dehydration, catalysed by enolaseGives PEP formation and bond energy raiseSo phosphoenolphruvate reacts with ADP
The kinase making ATP but NOT reversibly.
In anaerobiosis, pyruvate’s not the end;The problem we suppose is not hard to comprehend’
The dehydrogenation to phosphoglycerateWould grind to halt if NAD+ could not regenerate.
The answer is quite subtle, pryruvayte is reduced,Instead of malate shuttle, L-lactate is produced;Lactate dehydrogenase performs that noble feat,
NADH is oxidised; the pathway is complete.
The balance sheet you’ll see shows transfer of energy,Two ATPs from glucose, and three from G1P
That’s good, but oh to use the way where pyruvate’s reduced—With decarboxylation first, then ethanol produced!!!!!
Section 8.1: Glycolysis
The Fates of PyruvateThe Fates of PyruvatePyruvate is an energy-rich moleculeUnder aerobic conditions, pyruvate is converted to acetyl-CoA for use in the citric acid cycle and electron transport chain
Regulation of GlycolysisRegulation of GlycolysisThe rate of the glycolytic pathway in a cell is controlled by the allosteric enzymes:
Hexokinases I, II, and IIIPFK-1Pyruvate kinase
Allosteric enzymes are sensitive indicators of a cell’s metabolic state regulated locally by effector moleculesThe peptide hormones glucagon and insulin also regulate glycolysis
Regulation of Glycolysis ContinuedRegulation of Glycolysis ContinuedHigh AMP concentrations activate pyruvate kinaseFructose-2,6-bisphosphate, produced via hormone- induced covalent modification of PFK-2, activates PFK-1Accumulation of fructose-1,6-bisphosphate activates PFK-1 providing a feed-forward mechanism
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
GlycogenesisGlycogenesisSynthesis of glycogen, the storage form of glucose, occurs after a mealRequires 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 UDP-glucose from G1P by UDP-glucose phosphorylase
The phenomenon, in which glucose represses aerobic metabolism, is the Crabtree effectCrabtree effectRapid production of ethanol has the effect of eliminating microbial competitorsOnce glucose levels are depleted and O2 is available the yeast reabsorbs the ethanol and converts it to acetaldehyde for use as an energy source