Biochemistry and Molecular Biology Resource

 

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Eric C. Niederhoffer, Ph.D.

Associate Professor of Biochemistry and Molecular Biology

Southern Illinois University School of Medicine
600 Agriculture Drive, Carbondale, IL 62901-6503
Rm 112 Lindegren, 618-453-6467
eniederhoffer@siumed.edu
Copyright 2000- , E.C. Niederhoffer.
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Metabolic Pathways


Simplified metabolic pathways are summarized in this section. For more detailed information, please see any biochemistry textbook or use Biochemistry Animations or The Medical Biochemistry Page. Please note that red indicates molecule is used while green indicates molecule is produced.

Glycolysis is responsible for the oxidation of glucose into pyruvate. Pentose phosphate pathway serves several purposes, production of ribose-5-phosphate, NADPH and glycolytic intermediates (fructose and glyceraldehyde-3-phosphate). Glycogenesis and glycogenolysis are processes that synthesize the glucose storage macromolecule glycogen and degrade glycogen into glucose-1-phosphate (and glucose), respectively. Fructose metabolism occurs in muscle and liver. Tricarboxylic acid cycle generates reducing equivalents for the electron transport chain and processes various metabolytes from other pathways. The electron transport chain couples reducing equivalents with ATP production. Gluconeogenesis uses metabolytes to synthesize new glucose. Lipogenesis and lipolysis are processes that synthesize and degrade fatty acids. β-oxidation is responsible for the complete oxidation of fatty acids.

 

Glycolysis (glycolytic pathway)

This process, which may occur in all cells, involves splitting the 6-carbon monosaccharide into two 2-carbon molecules, dihydroxyacetone phosphate and glyceraldehyde-3-phosphate. Two ATP molecules are invested initially (hexokinase and phosphofructokinase-1) with the eventual net production of 2 ATP molecules (3-phosphoglycerate kinase and pyruvate kinase). Two NADH are produced by glyceraldehyde-3-phosphate dehydrogenase. The resulting NADH may be reoxidized by lactate dehydrogenase such that NAD+ is regenerated. Fructose can be processed by hexokinase to enter the glycolytic pathway as fructose-6-phosphate.

Glycolytic pathway

glycolytic pathway

 

Pentose phosphate pathway

The pentose phosphate pathway (also denoted as the hexose monophosphate shunt) provides NADPH (for reducing oxidized glutathione, for fatty acid and steroid synthesis, for other cytochrome P450 reactions), ribose-5-phosphate (for nucleotide base synthesis), and intermediates (fructose-6-phosphate and glyceraldehyde-3-phosphate) that can feed back into the glycolytic pathway.

Pentose phosphate pathway

pentose phosphate pathway

 

Glycogenesis and glycogenolysis

Glycogen is synthesized in many cells from glucose. There is extensive branching of glycogen that is important for creating many sites of action for the degrdation enzyme phosphorylase. Phosphorylase releases glucose-1-phosphate (90% of the time) while the debranching enzyme releases glucose (10% of the time).

Glycogenesis/glycogenolysis

glycogenesis/glycogenolysis

 

Fructose metabolism

In muscle, fructose may be phosphorylated by hexokinase to form fructose-6-phosphate and directly enter the glycolytic pathway. The liver has fructokinase, which synthesizes fructose-1-phosphate. Aldolase and triose kinase generate glyceraldehyde-3-phosphate and dihydroxyacetone phosphate. These intermediates can be directed towards storage as either glycogen or triacylglycerol. (Dashed lines indicate several steps not listed.)

Fructose metabolism (hepatic)

frucose metabolism

 

Tricarboxylic acid cycle (citric acid cycle)

The tricarboxylic acid cycle is responsible for oxidizing acetyl-CoA to CO2 and generating the reducing equivalents NADH and FADH2, which are shuttled to the electron transport chain for ATP production.. GTP is also produced. Intermediates of the cycle may be used to synthesize other biomolecules and metabolytes from other pathways may be incorporated into the cycle.

Tricarboxylic acid cycle (citric acid cycle)

tricarboxylic acid cycle

 

Electron transport chain

The electron transport chain is found in the mitochondrion and uses reducing equivalents (FADH2, NADH) to drive the formation of a H+ gradient. This gradient powers the synthesis of ATP. The four components are associated with the inner mitochondrial membrane. Complex I is NADH dehydrogenase; complex II is succinate dehydrogenase; complex III is cytochrome bc1; and complex IV is cytochrome c oxidase.

Electron transport chain

electron transport chain

 

Gluconeogenesis

New glucose can be synthesized from lactate, amino acids, glycerol, and odd-chain fatty acids. Gluconeogenesis requires enzymes (glucose-6-phosphatase, fructose-1,6-bisphosphatase, malate dehydrogenase, and phosphoenolpyruvate carboxykinase) to by-pass the three irreversible reactions (glucokinase, phosphofructokinase-1, and pyruvate kinase) of the glycolytic pathway. Lactate, glycine, serine, cysteine, and alanine are converted to pyruvate, which then enters the tricarboxylic acid cycle as oxaloacetate through the action of pyruvate carboxylase (requires ATP). Mitochondrial malate is transported to the cytosol where it is converted to oxaloacetate (malate dehydrogenase). Oxaloacetate enters the glycolytic pathway as phosphoenolpyruvate as catalyzed by phosphopyruvate carboxykinase (requires GTP). Asparate enters through cytosolic oxaloacetate, while phenylalanine and tyrosine enter through cytosolic malate. Glutamate, histidine, and proline enter through mitochondrial α-ketoglutarate, while isoleucine, methionine, and valine enter through mitochondrial succinyl-CoA. Glycerol is obtained from the hydrolysis of triacylglycerols (glycerol kinase requires ATP) and enters the glycolytic pathway as dihydroxyacetone phosphate. Odd chain fatty acids are converted to propionyl-CoA, which can then enter through mitochondrial succinyl-CoA. (Dashed lines indicate several steps not listed.)

Gluconeogenesis

gluconeogenesis

 

Lipogenesis and lipolysis

Lipid synthesis begins with the production of fatty acids from acetyl-CoA. ATP is used for the initial portion of the synthetic pathway. NADPH from the pentose phosphate pathway is used by enzymes (fatty acid synthase complex) associated with the pathway. Fatty acid synthase is a multienzyme complex with acyl carrier protein and the following activities: ketoacyl synthase, acetyl transacylase, malonyl transacylase, hydratase, enoyl reductase, ketoacyl reductase and thioesterase. Each light green box represents the repeating of steps from malonyl-CoA through acyl-ACP to generate a Cn+2 fatty acid. Triacylglycerol is formed by esterification of fatty acid with glycerol-3-phosphate. Lipolysis utilizes hormone-sensitive lipase (activated by epinephrine, glucagon, and cortisol) to hydrolyze triacylglycerol into glycerol and free fatty acids. (Dashed lines indicate several steps not listed.)

Lipogenesis and lipolysis

lipogenesis/lipolysis

 

β-oxidation

Fatty acids may be metabolized in the mitochondrion by β-oxidation to generate acetyl-CoA (processed by the tricarboxylic acid cycle), FADH2 and NADH, which can then be utilized by the electron transport chain to drive a H+ gradient and ATP synthesis. Each light green box represents the repeating of steps from Cn to Cn-2 fatty acid; each step creates FADH2, NADH, and acetyl-CoA. (Dashed lines indicate several steps not listed.)

Beta-oxidation

beta-oxidation

 

 

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