Branched pathway, control

C, for each enzyme in a pathway. This coefficient expresses the relative contribution of each enzyme to setting the rate at which metabolites flow through the pathway—that is, the flux, J. C can have any value from 0.0 (for an enzyme with no impact on the flux) to 1.0 (for an enzyme that wholly determines the flux). An enzyme can also have a negative flux control coefficient. In a branched pathway, an enzyme in one branch, by drawing intermediates away from the other branch, can have a negative impact on the flux through that other branch (Fig. 15-34). C is not a constant, and it is not... 

Metabolic control can be understood to some extent by focusing attention on those enzymes that catalyze rate-limiting steps in a reaction sequence. Such pacemaker enzymes1-4 are often involved in reactions that determine the overall respiration rate of a cell, reactions that initiate major metabolic sequences, or reactions that initiate branch pathways in metabolism. Often the first step in a unique biosynthetic pathway for a compound acts as the pacemaker reaction. Such a reaction may be described as the committed step of the pathway. It usually proceeds with a large decrease in Gibbs energy and tends to be tightly controlled. Both the rate of synthesis of the enzyme protein and the activity of the enzyme, once it is formed, may be inhibited by feedback inhibition which occurs when an end product of a biosynthetic pathway accumulates... 

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. 

In linear pathways, individual flux control coefficient will normally lie between zero (no control) and 1 (full control). But in branched pathways, negative flux control coefficients arise where the stimulation of an enzyme in one branch may decrease the flux through a competing branch. This gives rise to values greater than 1 occurring in that pathway. 

A brief sketch of what we know about the kinetics of RDX decomposition is needed for context for the discussion of the simulation studies. In most experiments the data are taken with little experimental control, with the observations complicated by the rapid release of large amounts of energy, and with the liquid or solid undergoing phase transitions and chemical reactions to form small gaseous molecules such as N2O, H20, H2CO, HCN, NO, N02, CO, and C02. The reaction mechanisms involve many sequential, branched pathways, which are strongly dependent on the experimental conditions. It is not our purpose here to try to sort out the mechanisms for the various conditions, but we do need, for foundation, to discuss the experimental observations relevant to the elementary gas-phase reactions. 

Most of the pathways of amino acid biosynthesis are regulated by feedback inhibition, in which the committed step is allosterically inhibited by the final product. Branched pathways require extensive interaction among the branches that includes both negative and positive regulation. The regulation of glutamine synthetase from if. coli is a striking demonstration of cumulative feedback inhibition and of control by a cascade of reversible covalent modifications. 

A substantial isotope effect is associated with Reaction (8), but the absence of a branching pathway means that the isotopic composition of I is effectively controlled by ] (Si = S]). The only effect of > 0 is to require that, at steady state, H is enriched relative to I. 

The pathway shown in Figure 10.3 is branched. If regulation were to occur at step 1 only, there would be no control over the production of X from B. If only step 2 were regulated, there would be no regulation over the production of X from A. Regulation at step 3 provides control of the amount of X produced from both A and B. In branched pathways, the principal regulatory step is usually after the branch point. 

Define the committed step of a metabolic pathway and recognize that it is often the target of feedback regulation. Note the main features of control of branched pathways by feedback inhibition and activation, enzyme multiplicity, and cumulative feedback. 

EXAMPLE 5.25 Control of a branched pathway is more complex than in Fig. 5-18. Consider the metabolic scheme in Fig. 5-19. Here, B reacts with C, while D is prodnced 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 were supplied from an external source so that [B] [C], then B would inhibit its own synthesis from A and the concentrations of B and C would tend to become equal. 

A variety of patterns of end-product inhibition have been described [5,69] (1) In enzyme multiplicity inhibition balanced control of an early enzyme of the common part of a branched pathway is obtained because the enzyme is present in the form of several isoenzymes, each specifically inhibited by an end product of one of the branches. (2) In cumulative feedback inhibition an enzyme which mediates the formation of a product used in many pathways is partly inhibited by individual end products of the pathways. Each inhibitor adds its effect to the total inhibition, but the combined effect is less than the sum of the single inhibitions. (3) In concerted feedback inhibition two or more end products are required to act together before any significant inhibition is exhibited. (4) In cooperative feedback inhibition several end products can act as partial inhibitors of an enzyme, but a mixture of two different inhibitors results in greater inhibition than the sum of the individual inhibitions. (5) The term sequential feedback inhibition refers to inhibition of an early enzyme by an intermediate whose accumulation is controlled by inhibition of one or more late pathway enzymes by the end product [71 ]. 

The feedback inhibition control described above provides one form of regulation of the synthesis of chorismic acid which serves as a substrate in the first reaction specific to the tryptophan branch pathway. In the same reaction glutamine serves as the amino donor [80,81] in the... 

Many plants utilize different PAL isoforms for stress responses or for biosynthesis of structural components, and these different PALs exhibit differential expression in distinct tissues. Metabolic channeling may help control the flux of phenylalanine through PAL into the different phenylpropanoid branch pathways [6,7]. 

Bennett, T. et al. (2006) The Arabidopsis MAX pathway controls shoot branching by regulating auxin transport. Current Biology 16, 553-563... 

Homocysteine biosynthesis requires the confluence of two pathways, one providing the 4-carbon moiety via 0-phosphohomo-serine, the other providing the sulfur moiety via cysteine (Fig. 3), Sach of the converging pathways contains two branch points, and additional branch points occur at threonine, methionine and AdoMet. A priori, two predictions can be made regarding the control patterns of homocysteine biosynthesis in the system. One is that the control patterns will be complex, in order that a fine balance can be maintained between the interlocking and multiply branched pathways. The second is that novel control patterns may occur... 

Mechanisms operating in the control of branched pathways have been studied extensively in bacterial amino acid biosynthesis. 

For dealing with such complex regulatory situations, nature appears to have invented two principal devices. One is multivalent repression or inhibition of the enzyme catalyzing the committed step. Each of the several end products of the branched pathway inhibits the enzyme or its synthesis partially but the effects are additive. Alternatively, the enzyme catalyzing the committed step may exist in multiple forms, each susceptible to one end product of the branched pathway but not to others. It, therefore, seems entirely possible that the microsomal HMG-CoA reductase is either subject to multiple end product inhibition or that it exists in several independent forms. Since we are dealing with the control of HMG-CoA reductase synthesis rather than allosteric regulation of enzyme activity, no easy solution of this problem is in sight. 

Other possible choices are to use two pairs of frequencies which together have the same energies. The key point is that quantum interference between the two pathways can be used to control the branching ratio. This coherent-control approach is very general and can be used in virtually any branch of molecular dynamics, including scattering and photo-dissociation. 

Hundreds of metabohc reac tions take place simultaneously in cells. There are branched and parallel pathways, and a single biochemical may participate in sever distinct reactions. Through mass action, concentration changes caused by one reac tion may effect the kinetics and equilibrium concentrations of another. In order to prevent accumulation of too much of a biochemical, the product or an intermediate in the pathway may slow the production of an enzyme or may inhibit the ac tivation of enzymes regulating the pathway. This is termed feedback control and is shown in Fig. 24-1. More complicated examples are known where two biochemicals ac t in concert to inhibit an enzyme. As accumulation of excessive amounts of a certain biochemical may be the key to economic success, creating mutant cultures with defective metabolic controls has great value to the produc tion of a given produc t. 

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