Medical genetics / edited by Victor A. McKusick and Robert Claiborne.

Date:
[1973]
Catalogue details

Licence: Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)

Credit: Medical genetics / edited by Victor A. McKusick and Robert Claiborne. Source: Wellcome Collection.

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    LEYERE AND KAPPAS Schematic depicts the control mechanism through which heme synthesis is regulated in liver cells, as postulated by Granick. In this formulation, production of ALA synthe¬ tase is governed by a represser-operator mechanism. The repressor consists of an apore- pressor protein, with heme acting as a corepressor. When heme is displaced from its binding site by a steroid or drug, the repressor is inactivated, the structural gene for ALA synthetase can code for more messenger RNA, and more enzyme is synthesized. The concentration of active inducers in the cell may be dependent on the rate at which they are inactivated by chemical transformation (oxidation, conjugation, etc.). In liver cells, feedback repression of ALA synthetase formation by heme appears to be the principal control; in erythroid cells, feedback inhibition of the enzyme may be the control for heme synthesis. Recent evidence suggests certain inducers effect translational rather than transcriptional mechanisms in regulating ALA synthetase. porphyrin synthesis. It seems difficult to postulate a single mechanism of ac¬ tion shared by the wide variety of chemicals that induce ala synthetase and which is also consistent with the known genetic transmission of the human disease as an autosomal domi¬ nant trait. A framework for a possible expla¬ nation of this problem may exist in an analogy with microbial genetics, in which the existence of a genetic con¬ trol mechanism responsive to induc¬ tion and repression is presupposed. A regulator gene is postulated that makes a protein (aporepressor) with a prosthetically specific component (co¬ repressor ) that acts to repress the op¬ erator gene that directly determines the rate at which a structural gene codes for a specific enzyme. The result is to slow down the rate at which the structural gene communicates its in¬ formation to the nucleic acids, which in turn results in diminished synthesis of enzymes. It has been postulated by Granick that there is such a repressor system controlling heme synthesis in the liver and that heme, the end prod¬ uct of the pathway, is a corepressor in this control system, thus regulating the rate of its own formation. It may be further postulated that the diverse assortment of chemicals that excite porphyrin synthesis do so by affecting the repressor portion of the system-that entity of which heme is a prosthetic component. These in¬ ducer chemicals, which include many drugs and steroids, may block or dis¬ place heme from its binding site on the aporepressor protein — perhaps by changing its configuration — thus ren¬ dering the repressor inoperative. If the repressor system does not work, the structural gene then proceeds at its own high intrinsic rate, for transmis¬ sion of genetic information, thus lead¬ ing to an enhanced formation of л l л synthetase. Since the other enzymes in this pathway are nonlimiting, this would lead to overproduction of heme precursors. In hereditary porphyria (aip), a genetic lesion, possibly a defective operator gene, results in the control mechanism for ala synthe¬ tase being less repressed than nor¬ mally and responding inappropriately to various drugs. This lesion is mani¬ fested by an increased formation of ALA synthetase, and a high level of this enzyme activity in the liver now appears to be a characteristic abnor¬ mality in AI p patients. Recently, a decreased activity of p в G deaminase has been demonstrated in the erythrocytes and liver cells of patients with aip. In addition, a de¬ crease in the activity of this enzyme has been noted in the red blood cells of some asymptomatic family mem¬ bers. In our own studies of ai p family lineages, decreased p в g deaminase in red blood cells has been found in a group of prepubertal children in whom the clinical syndrome is, as we have noted above, never manifest. It has been suggested by some investigators that this low p в g deaminase activity reflects the primary gene defect in ai p and leads to a decrease in heme syn¬ thesis in liver cells. The postulated deficiency of heme synthesis deprives the aporepressor of its corepressor (heme) and thus secondarily causes an increase in a la synthetase produc¬ tion. A deficiency in hepatic heme syn¬ thesis in the liver of ai p patients has, however, not yet been proven. More¬ over, the decrease in p в G deaminase activity averages only about 50% of normal and there is, as yet, no demon¬ strated decrease in heme-proteins such as cytochrome P-450 in the livers of 118