Carbohydrate Metabolism: Glucose Structure and Fates

Glucose occupies a central position in the metabolism of plants, animals, and microorganisms.
It is a good fuel due to its relatively high potential energy content.
Glucose is stored as a high molecular weight polymer, such as glycogen, to maintain a relatively low cytosolic osmolarity.

Glucose can be stored as a polysaccharide or sucrose.
It can be oxidized to a three-carbon compound (pyruvate) via glycolysis to produce ATP and metabolic intermediates.
Glucose can be oxidized via the pentose phosphate pathway to yield ribose 5-phosphate for nucleic acid synthesis and NADPH for reductive biosynthetic processes.

Also known as the Embden-Meyerhof-Parnas pathway.
Occurs in the cytoplasm.
A molecule of glucose is degraded in a series of enzyme-catalyzed reactions to yield:
- Two molecules of the three-carbon compound, pyruvate.
- Some free energy released from glucose conserved in the form of ATP and NADH.

Aerobic glycolysis: involves a sequence of 10 steps, and pyruvate is the end product, which is then converted to acetyl CoA (a major fuel for the citric acid cycle) by oxidative decarboxylation.
Anaerobic glycolysis: glucose is converted to pyruvate, which is reduced by NADH to form lactate, allowing for continued production of ATP in tissues that lack mitochondria or are deprived of sufficient oxygen.

The conversion of glucose to pyruvate occurs in two stages:
- Energy investment phase (first five reactions): the phosphorylated form of intermediates are synthesized at the expense of ATP.
- Energy generation phase (last five reactions): a net of 2 molecules of ATP and NADH are formed by substrate-level phosphorylation per glucose molecule metabolized while generating pyruvate.

1. Phosphorylation of glucose to glucose-6-phosphate.
1. Conversion of glucose-6-phosphate to fructose-6-phosphate.
1. Phosphorylation of fructose-6-phosphate to 1,6-bisphosphate.
1. Cleavage of fructose 1,6-bisphosphate to form two different triose phosphates.
1. Interconversion of the triose phosphates.
1. Oxidation of glyceraldehyde 3-phosphate to 1,3-bisphosphoglycerate.
1. Phosphoryl transfer of 1,3-bisphosphoglycerate to ADP to form 3-phosphoglycerate.
1. Conversion of 3-phosphoglycerate to 2-phosphoglycerate.
1. Dehydration of 2-phosphoglycerate to phosphoenolpyruvate.
1. Transfer of the phosphoryl group from phosphoenolpyruvate to ADP yielding pyruvate.

1. Oxidative decarboxylation of pyruvate to acetyl CoA in tissues with a high oxidative capacity.
1. Reduction to lactate via lactic acid fermentation.
1. Reduction to ethanol in yeast and certain microorganisms.

Anaerobic glycolysis: 2 molecules of ATP are generated for each molecule of glucose converted to 2 molecules of lactate.
Aerobic glycolysis: 2 molecules of ATP are generated for each molecule of glucose, and 2 molecules of NADH are produced.

Gluconeogenesis is a ubiquitous multistep process in which pyruvate, or a related three-carbon compound, is converted to glucose.
Seven of the steps are catalyzed by the same enzymes used in glycolysis.
Three irreversible steps in the glycolytic pathway are bypassed by reactions catalyzed by gluconeogenic enzymes.

Allosteric regulation of the enzymes that catalyze the three irreversible reactions: hexokinase, phosphofructokinase-1, and pyruvate kinase.
Regulation of phosphofructokinase-1 by:
- Energy levels within the cell.
- Fructose 2,6-bisphosphate.
Covalent modulation of pyruvate kinase.
Fed-forward regulation: increased fructose 1,6-bisphosphate activates pyruvate kinase.### Hormonal Regulation of Glycolysis
Glucagon inhibits hepatic glycolysis and stimulates gluconeogenesis by dephosphorylating pyruvate kinase, reactivating the enzyme.
Regular consumption of carbohydrate-rich meals or administration of insulin increases the amount of glucokinase, phosphofructokinase, and pyruvate kinase.
This results in a 10- to 20-fold increase in enzyme activity, which typically occurs over hours to days.
High activity of these three enzymes favors the conversion of glucose to pyruvate, a characteristic of the well-fed state.

Glucagon stimulates gluconeogenesis by:
- Lowering the level of fructose 2,6-bisphosphate, resulting in the activation of fructose 1,6-bisphosphatase and inhibition of fructokinase.
- Covalently modifying enzyme activity, specifically the conversion of pyruvate kinase to its inactive (phosphorylated) form, which diverts PEP to glucose synthesis.
- Inducing the transcription of the PEP carboxykinase gene, increasing the availability of this enzyme's activity.
Substrate availability, particularly glucogenic amino acids, significantly influences the rate of hepatic glucose synthesis.
Decreased levels of insulin favor the mobilization of amino acids from muscle protein, providing the carbon skeleton for gluconeogenesis.
Allosteric inhibition by AMP inhibits fructose 1,6-bisphosphatase.
Allosteric activation of hepatic pyruvate carboxylase by acetyl CoA occurs during fasting, resulting from excessive lipolysis in adipose tissue.