Metabolism adaptive enzymes

It has been known for some time that bacteria can alter their enzyme composition in response to changes in their environment. Early studies demonstrated that certain enzymes in microorganisms were produced in significant amounts only when their substrates were present in the culture medium. Such enzymes were considered a special group and were first called "adaptive" enzymes now they are called inducible enzymes because they are formed de novo from amino acids rather than from protein precursors. Opposed to the inducible enzymes were the constitutive enzymes, which were formed in constant amounts regardless of the metabolic state of the organism. 

Adaptive Enzyme Theory. The aliesterases are largely found in the microsomes of rat liver cells (44). Recently Hart and Fouts (51,52, 67-69) have presented evidence that in vivo administration of chlordan or chemically related DDT stimulates the activity of hepatic microsomal drug-metabolizing enzymes, as evidenced by proliferation of smooth-surfaced endoplasmic reticulum (SER) which was first noted with phenobarbital. Several reviews of hepatic drug metabolism... 

Figure 16.23. Alteration of Gene Expression in Tumors Due to Hypoxia. The hypoxic conditions inside a tumor mass lead to the activation of the hypoxia-inducible transcription factor (HIF-1), which induces metabolic adaptation (increase in glycolytic enzymes) and activates angiogenic factors that stimulate the growth of new blood vessels. [Adapted from C. V. Dang and G. L. Semenza. Trends Biochem. Sci. 24(1999) 68-72.]...

Tolerance also results from metabolic changes (enzyme induction) and physiological/behavioural adaptation to drug effects, e.g. opioids. Physical dependence develops to a substantial degree with... 

Hydroxykynurenine excretion in pathological states was also first reported by Japanese workers (573), who identified it as the substance causing the diazo reaction and the Weiss urochromogen reaction in urines from cases of severe tuberculosis. This was confirmed in the author s laboratory (178), where it was also shown that the excretion is unrelated to tuberculosis as such. Hydroxykynurenine excretion occurs in a large proportion of patients with fevers of varying etiology and is in all probability due to the increased rate of breakdown of body proteins in fever. Presumably the protein breakdown induces an adaptive increase in tryptophan peroxidase-oxidase, and the capacity of the available kynureninase, which comes later in the metabolic chain and is not an adaptive enzyme (480), is exceeded. 

An additional strategy that enhances metabolic adaptability is evolution of alternative enzymes that synthesize the same product using different substrates (see Table 1). Alternative enzymes allow bacteria to take advantage of reactants that may be in sufficient supply only occasionally in a fluctuating environment. For example, E. coli contains two enzymes that catalyze oxidative decarboxylation of coproporphyrinogen III to form protoporphyrinogen IX in the heme biosynthesis pathway. FlemF uses O2 HemN is a radical 5-adenosylmethionine enzyme that catalyzes a complex 02-independent reaction. HemN contains an 02-sensitive Fe-S cluster. HemN is active only under anoxic conditions, and HemF is active only when O2 is available, but E. coli is able to synthesize heme in either case. 

There are two points to note carefully (1) Phosphorylation occurs specifically at C-6, the carbon furthest from the carbonyl group (Fig. 22-2), and (2) only the d carbohydrate isomers are involved in metabolism. In the future, we will omit the conformational identity from these equations for convenience only. It is critical to note that this reaction, like all others of metabolism, require a specific enzyme in order to proceed at a rate appropriate to the temperature and time requirements of metabolism. The enzyme is specific with respect to two issues (1) the transfer of a phosphate group (all enzymes specific for the transfer of a phosphate group are called kinases), and (2) the enzyme is selectively adapted to hexose sugars. 

Fig. 4.22. Hypoxia-mediated metabolic adaptation for energy preservation. Activation of genes for glucose transporter-1 (GLUT-1 = 1) and glycolytic enzymes yields an increased glycolytic rate. H -ions produced are preferentially exported via a Na /H -antiporter (NHE-1 = 3) and a lactate /H -symporter (monocarboxylate transporter MCT-1 = 2) leading to a drop in extracellular pH (pH.). Low extracellular pH activates the membrane-bound ectoenzyme carbonic anhydrase IX (CA IX = 4). Key mechanism regulating intracellular pH in tumor cells when protons are produced is also shown (Na -depen-dent HCOs" /CL -exchanger = 5). HIF-Ia = hypoxia-inducible factor la, PHDs = prolyl hydroxylases, FIH = asparagyl hydroxylase, lac" = lactic acid...

Among saprophytic fungi there are several well-recognized types of physiology which center around the presence of particular constitutive or adaptive enzyme systems. For example, there are saprophytes that can metabolize simple carbohydrates only, such as glucose those that can metabolize higher carbohydrates, such as starch or other polysaccharides, and those that, although they may normally metabolize the simple carbohydrates, seem to have an adaptive enzyme system that can incorporate a polysaccharide substrate if simpler forms of carbohydrate are not available. 

Here, then, we have examples of the regulation of metabolism by a promotion or suppression of enzyme synthesis. What is not yet fully understood is how inducers promote and repressors inhibit the synthesis of new enzyme protein. When two inducer molecules are supplied simultaneously and when the rate of protein synthesis is limited by nitrogen supply then it is possible to demonstrate competition between the systems synthesising the adaptive enzymes in so far as one enzyme is synthesised the amount of the second enzyme formed is correspondingly reduced. Secondly, induction of an enzyme can sometimes be effected by a compound (chemically similar to the substrate) but not acted upon by the enzyme whereas other molecules which can act as substrates for the enzyme may be ineffective as inducers. Thus methyl-/S-o-thiogalactoside is a powerful inducer... 

A knowledge of normal metabohsm is essential for an understanding of abnormalities underlying disease. Normal metabolism includes adaptation to periods of starvation, exercise, pregnancy, and lactation. Abnormal metabolism may result from nutritional deficiency, enzyme deficiency, abnormal secretion of hormones, or the actions of drugs and toxins. An important example of a metabolic disease is diabetes mellitus. 

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