The Flux Of Metabolites In Metabolic Pathways Must Be Regulated In A Concerted Manner

Regulation of the overall flux through a pathway is important to ensure an appropriate supply, when required, of the products of that pathway. Regulation is achieved by control of one or more key reactions in the pathway, catalyzed by "regulatory enzymes." The physicochemical factors that control the rate of an

Figure 15-7. Intracellular location and overview of major metabolic pathways in a liver parenchymal cell. (AA metabolism of one or more essential amino acids; AA metabolism of one or more nonessential amino acids.)

enzyme-catalyzed reaction, eg, substrate concentration, are of primary importance in the control of the overall rate of a metabolic pathway (Chapter 9).

"Nonequilibrium" Reactions Are Potential Control Points

In a reaction at equilibrium, the forward and reverse reactions occur at equal rates, and there is therefore no net flux in either direction:

In vivo, under "steady-state" conditions, there is a net flux from left to right because there is a continuous supply of A and removal of D. In practice, there are invariably one or more nonequilibrium reactions in a metabolic pathway, where the reactants are present in concentrations that are far from equilibrium. In attempting to reach equilibrium, large losses of free energy occur as heat, making this type of reaction essentially irreversible, eg,

Inactive Enz,

Ca2+/calmodulin

Cell membrane

Cell membrane

Negative allosteric feed-back inhibition

Ribosomal synthesis of new enzyme protein

Negative allosteric feed-back inhibition

Ribosomal synthesis of new enzyme protein

Nuclear production of mRNA

Repression

Induction

Repression

Figure 15-8. Mechanisms of control of an enzyme-catalyzed reaction. Circled numbers indicate possible sites of action of hormones. CD, Alteration of membrane permeability; conversion of an inactive to an active enzyme, usually involving phosphorylation/dephosphorylation reactions; CD, alteration of the rate of translation of mRNA at the ribosomal level; induction of new mRNA formation; and CD, repression of mRNA formation. CD and CD are rapid, whereas CD-CD are slower ways of regulating enzyme activity.

Such a pathway has both flow and direction. The enzymes catalyzing nonequilibrium reactions are usually present in low concentrations and are subject to a variety of regulatory mechanisms. However, many of the reactions in metabolic pathways cannot be classified as equilibrium or nonequilibrium but fall somewhere between the two extremes.

The Flux-Generating Reaction Is the First Reaction in a Pathway That Is Saturated With Substrate

It may be identified as a nonequilibrium reaction in which the Km of the enzyme is considerably lower than the normal substrate concentration. The first reaction in glycolysis, catalyzed by hexokinase (Figure 17-2), is such a flux-generating step because its Km for glucose of 0.05 mmol/L is well below the normal blood glucose concentration of 5 mmol/L.

ALLOSTERIC & HORMONAL MECHANISMS ARE IMPORTANT IN THE METABOLIC CONTROL OF ENZYME-CATALYZED REACTIONS

A hypothetical metabolic pathway is shown in Figure 15-8, in which reactions A O B and C O D are equilibrium reactions and B ^ C is a nonequilibrium reaction. The flux through such a pathway can be regulated by the availability of substrate A. This depends on its supply from the blood, which in turn depends on either food intake or key reactions that maintain and release substrates from tissue reserves to the blood, eg, the glycogen phosphorylase in liver (Figure 18-1) and hormone-sensitive lipase in adipose tissue (Figure 25-7). The flux also depends on the transport of substrate A across the cell membrane. Flux is also determined by the removal of the end product D and the availability of cosubstrate or cofactors represented by X and Y. Enzymes catalyzing nonequilibrium reactions are often allosteric proteins subject to the rapid actions of "feedback" or "feed-forward" control by allosteric modifiers in immediate response to the needs of the cell (Chapter 9). Frequently, the product of a biosynthetic pathway will inhibit the enzyme catalyzing the first reaction in the pathway. Other control mechanisms depend on the action of hormones responding to the needs of the body as a whole; they may act rapidly, by altering the activity of existing enzyme molecules, or slowly, by altering the rate of enzyme synthesis.

SUMMARY

• The products of digestion provide the tissues with the building blocks for the biosynthesis of complex molecules and also with the fuel to power the living processes.

• Nearly all products of digestion of carbohydrate, fat, and protein are metabolized to a common metabolite, acetyl-CoA, before final oxidation to CO2 in the citric acid cycle.

• Acetyl-CoA is also used as the precursor for biosynthesis of long-chain fatty acids; steroids, including cholesterol; and ketone bodies.

• Glucose provides carbon skeletons for the glycerol moiety of fat and of several nonessential amino acids.

• Water-soluble products of digestion are transported directly to the liver via the hepatic portal vein. The liver regulates the blood concentrations of glucose and amino acids.

• Pathways are compartmentalized within the cell. Glycolysis, glycogenesis, glycogenolysis, the pentose phosphate pathway, and lipogenesis occur in the cy-tosol. The mitochondrion contains the enzymes of the citric acid cycle, P-oxidation of fatty acids, and of oxidative phosphorylation. The endoplasmic reticu-lum also contains the enzymes for many other processes, including protein synthesis, glycerolipid formation, and drug metabolism.

• Metabolic pathways are regulated by rapid mechanisms affecting the activity of existing enzymes, eg, allosteric and covalent modification (often in response to hormone action); and slow mechanisms affecting the synthesis of enzymes.

REFERENCES

Cohen P: Control of Enzyme Activity, 2nd ed. Chapman & Hall, 1983.

Fell D: Understanding the Control of Metabolism. Portland Press, 1997.

Frayn KN: Metabolic Regulation—A Human Perspective. Portland Press, 1996.

Newsholme EA, Crabtree B: Flux-generating and regulatory steps in metabolic control. Trends Biochem Sci 1981;6:53.

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Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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