Sequential feedback

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. 

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. 

Fig. 1. Feedback inhibition (a) and sequential feedback inhibition (b) in metabolic pathways.

The reaction scheme in Fig. 9-17 depicts isoleucine (E) synthesis from aspartate (A) by the bacterium Rhodopseudomonas spheroides. The control is called sequential feedback control. Describe the operation of this metabolic control system. 

Overproduction of E (isoleucine) inhibits enzyme E6 (threonine deaminase), and the consequent rise of D (threonine) reduces the rate of production of C (homoserine) via enzyme E3 (homoserine dehydrogenase). The concentration of B (aspartate semialdehyde) rises, and this in turn inhibits Ej (aspartokinase). It is therefore obvious why the control system is called a negative feedback network, or sequential feedback system. 

Y could inhibit the C —> D step, Z could inhibit the C — F step, and C could inhibit A —> B. This scheme is an example of sequential feedback inhibition. Alternatively, Y could inhibit the C —> D step, Z could inhibit the C —> F step, and the A —> B step would be inhibited only in the presence of both Y and Z. This scheme is called concerted feedback inhibition. 

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 ]. 

End-product inhibition of AS activity by tryptophan appears to be a rather common control mechanism among microorganisms. Nester and Jensen [71] described tryptophan inhibition of B. subtilis AS activity as the first step in sequential feedback control. Excess tryptophan would result in inhibition of the conversion of chorismate to anthrani-late. The consequent accumulation of chorismic acid would then serve as a feedback inhibitor of the DAMPS, the first enzyme in the pathway leading to chorismate synthesis. Bacillus alvei has an anthranilate synthetase which is extremely sensitive to inhibition by tryptophan [98]. In contrast to the mode of AS feedback inhibition in E. coli and S. typhimurium, the B. alvei AS is inhibited by tryptophan noncom-petitively with respect to chorismate and uncompetitively with respect to glutamine. It is the only Bacillus species, among 21 studied, which did not exhibit a sequential feedback control pattern [79]. 

In chapter 7, a method to control shape of deformable machine is studied. Control law is derived from the model. Experimental setup is of Part I in order to keep the condition simple. By carefully changing the normal condition of input, undiscovered shapes are derived. The assumption was challenged that controlling active material requires sequential feedback to counteract the unreliability. 

Weber, G., Lea, M. A., and Stamm, N. B., 1968, Sequential feedback inhibition and regulation of liver carbohydrate metabolism through control of enzyme activity, Adv. Enzyme Regul. 6 101. 

Blending also plays a role in the chemical industry. The use of Raman spectroscopy to control gasoline blending, particularly oxygenated species such as methanol, ethanol, propanols, and butanols, is discussed in US patent 5,596,196.64 The system can be operated in a feed-forward and/or feedback control scheme. In feed-forward, the composition of each of six remote feed tanks is measured sequentially. A control computer then... 

Figure 3. ITC-measurement of the complexation of (-)camphor by a-cyclodextrin in water. Left Primary heat pulse trace (CFB = cell feedback current) the saw-tooth shape arises from changing the aliquots of titrand solution. Right The time integral of the heat pulses furnishes the titration curve. The solid line represents the best fit to a 2 1 host-guest sequential binding model.

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