Branched metabolic pathways

FIGURE 15-34 Flux control coefficient, C, in a branched metabolic pathway. In this simple pathway, the intermediate B has two alternative fates. To the extent that reaction B —> E draws B away from the pathway A —> D, it controls that pathway, which will result in a negative flux control coefficient for the enzyme that catalyzes step B —> E. Note that the sum of all four coefficients equals 1.0, as it must. 

The rates of enzyme-catalyzed reactions in biological systems are altered by activators and inhibitors, collectively known as effector molecules. In metabolic pathways, the end-product often feedback-inhibits the committed step earlier on in the same pathway to prevent the build up of intermediates and the unnecessary use of metabolites and energy. For branched metabolic pathways a process of sequential feedback inhibition often operates. 

Control in branched metabolic pathways is more complex. Consider the metabolic scheme in Fig. 9-6. Here, B reacts with C, and D is produced further along the pathway for most effective control of D, B should inhibit the first enzyme (E,) and C should activate it. In this case, if B is supplied from an external source so that B > C, then B would inhibit its own synthesis from A and the concentration of B and C would tend to become equal. 

If one considers, in a complex system, a branched metabolic pathway with the intermediate metabolites and the end products Pi-)-n in which an inhibitor is assumed to interfere with the conversion of M3 to (Fig. 1), one should be able to verify the following predictions ... 

Thousands of reactions mediated by an equal number of enzymes are occurring at any given instant within the cell. Metabolism has many branch points, cycles, and interconnections, as a glance at a metabolic pathway map reveals... 

FIGURE 19.5 Glucose-6-phosphate is the branch point for several metabolic pathways. 

Peroxisomes are single-membrane, typically spherical, organelles ranging in size from 0.1-1 pm in diameter and numbering from a few hundred to a few thousand in mammalian cells [8]. The matrix contains 50 or more enzymes that participate in various metabolic pathways particularly those involved in the [3-oxidation of straight and 2-methyl branched very-long-chain and long-chain... 

In the first step of the reductive branch of this metabolic pathway three out of four methyl groups are transferred from methanol to CoM-SH (13) by methyl transferases, with formation of methyl-S-CoM (21) (Scheme 1) [21]. The transformation of 21 and CoB-SH (15) into methane and CoB-S-S-CoM (22) is catalyzed by the methyl-CoM reductase. Again, reductive cleavage of 22 is mediated by the heterodisulfide reductase [22]. The oxidative part involves oxidation of... 

Ibrahim, R.K. and Muzac, L, The methyltransferase gene superfamily a tree with multiple branches, in Evolution of Metabolic Pathways, Romeo, J.T., Ibrahim, R., Varin, L., and De Luca, V., Eds., Elsevier Science Ltd, Oxford, 2000, 349. 

Holms, W.H. (1986) The central metabolic pathways of Escherichia coli relationship between flux and control at a branch point, efficiency of conversion to biomass, and excretion of acetate. Curr. Top. Cell. Regul 28, 69-106. 

When Rinaldo analyzed Ryan s blood serum, he found high concentrations of methylmalonic acid, a breakdown product of the branched-chain amino acids isoleucine and valine, which accumulates in MMA patients because the enzyme that should convert it to the next product in the metabolic pathway is defective. And particularly telling, he says, the child s blood and urine contained massive amounts of ketones, another metabolic consequence of the disease. Like Shoemaker, he did not find any ethylene glycol in a sample of the baby s bodily fluids. The bottle couldn t be tested, since it had mysteriously disappeared. Ri-naldo s analyses convinced him that Ryan had died from MMA, but how to account for the results from two labs, indicating that the boy had ethylene glycol in his blood Could they both be wrong ... 

A small number of other biosynthetic pathways, which are used by both photosynthetic and nonphotosynthetic organisms, are indicated in Fig. 10-1. For example, pyruvate is converted readily to the amino acid t-alanine and oxaloacetate to L-aspartic acid the latter, in turn, may be utilized in the biosynthesis of pyrimidines. Other amino acids, purines, and additional compounds needed for construction of cells are formed in pathways, most of which branch from some compound shown in Fig. 10-1 or from a point on one of the pathways shown in the figure. In virtually every instance biosynthesis is dependent upon a supply of energy furnished by the cleavage to ATP. In many cases it also requires one of the hydrogen carriers in a reduced form. While Fig. 10-1 outlines in briefest form a minute fraction of the metabolic pathways known, the ones shown are of central importance. 

The pathways to amino acids arise as branchpoints from a few key carbohydrate intermediates in the central metabolic pathways. The common starting point for a branched pathway leading to several amino acids defines a family. 

As many metabolic pathways are branched, feedback inhibition must allow the synthesis of one product of a branched pathway to proceed even when another is present in excess. Here a process of sequential feedback inhibition may operate where the end-product of one branch of a pathway will inhibit the first enzyme after the branchpoint (the conversion of C to D or C to E in Fig. lb). When this branchpoint intermediate builds up, it in turn inhibits the first committed step of the whole pathway (conversion of A to B in Fig. lb). Since the end-product of a metabolic pathway involving multiple enzyme reactions is unlikely to resemble the starting compound structurally, the end-product will bind to the enzyme at the control point at a site other than the active site. Such enzymes are always allosteric enzymes. 

Some metabolic pathways are linear, some are cyclic, and some are branched, yielding multiple end products from a single precursor or converting several precursors into a single product. 

Some catabolic reactions of amino acid carbon chains are easy transformations to and from TCA cycle intermediates—for example, the transamination of alanine to pyruvate. Reactions involving 1-carbon units, branched-chain, and aromatic amino acids are more complicated. This chapter starts with 1-carbon metabolism and then considers the catabolic and biosynthetic reactions of a few of the longer side chains. Amino acid metabolic pathways can present a bewildering amount of material to memorize. Perhaps fortunately, most of the more complicated pathways lie beyond the scope of an introductory course or a review such as this. Instead of a detailed listing of pathways, this chapter concentrates on general principles of amino acid metabolism, especially those that occur in more than one pathway. 

IBRAHIM, R. K., MUZAK, I., The methyltransferase gene superfamily A tree with multiple branches, in Recent Advances in Phytochemistry Evolution of Metabolic Pathways (J. T. Romeo, R. I., Luc Varin, and V. De Luca, eds,), Elsevier Science Ltd., Oxford, 2000 pp. 349-384... 

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