Inhibition Jacob

There is evidence that protease inhibitors selectively regulate the activity of specific digestive enzymes at the level of gene expression (Rosewicz et al., 1989). Specifically, soybean trypsin inhibitor increases secretion of proteases, including a form of trypsin that is resistant to inhibition but does not cause an increase in amylase secretion. Although the relationships between protease inhibitors and exocrine pancreatic secretion have received the most attention, pancreatic secretion is increased when potato fiber is added to the diet (Jacob et al., 2000), although the mechanism and signaling pathway have not been elucidated. 

Andrews, Fi.E., Bruckdorfer, K.R., Dunn, R.C. and Jacobs, M. (1987). Low-density lipoproteins inhibit endothelium-dependent relaxation in rabbit aorta. Nature (Lond.) 327, 237-239. 

Jacobs, B. C., O Hanlon, G. M., Bullens, R. W. M., Veitch, J., Plomp, J. J. and Wilhson, H. J. Immunoglobulins inhibit pathophysiological effects of anti-CQlb-positive sera at motor nerve terminals through inhibition of antibody binding. Brain 126 2220-2234,2003. 

These studies suggest that there are substance(s) in tobacco smoke, as yet unidentified, that inhibit the metabolism of nicotine. Because nicotine and cotinine are metabolized by the same enzyme, the possibility that cotinine might be responsible for the slowed metabolism of nicotine in smokers was examined. In a study in which nonsmokers received an intravenous infusion of nicotine with and without pretreatment with high doses of cotinine, there was no effect of cotinine on the clearance of nicotine (Zevin et al. 1997). Also, carbon monoxide at levels and in patterns similar to those experienced during smoking had no effect on nicotine and cotinine clearance (Benowitz and Jacob 2000). 

Benowitz NL, Herrera B, Jacob P, 3rd (2004) Mentholated cigarette smoking inhibits nicotine metabohsm. J Pharmacol Exp Ther 310 1208-1215... 

It was snbseqnently discovered that the first enzyme in the pathway for isoleucine synthesis, which is threonine deaminase, was inhibited by isoleucine in an extract of E. coli. No other amino acid caused inhibition of the enzyme. Threonine deaminase is, in fact, the rate-limiting enzyme in the pathway for isoleucine synthesis, so that this was interpreted as a feedback control mechanism (Fignre 3.13(a)). Similarly it was shown that the hrst enzyme in the pathway for cytidine triphosphate synthesis, which is aspartate transcarbamoylase, was inhibited by cytidine triphosphate (Fignre 3.13(b)). Since the chemical structures of isoleucine and threonine, or cytidine triphosphate and aspartate, are completely different, the qnestion arose, how does isolencine or cytidine triphosphate inhibit its respective enzyme The answer was provided in 1963, by Monod, Changenx Jacob. 

Jackson D, Stachowiak MK, Bruno JP, et al Inhibition of striatal acetylchohne release by endogenous serotonin. Brain Res 457 259-266, 1988 Jacobs S, Hansen F, Kasl S, et al Anxiety disorders during acute bereavement risk and risk factors. J Clin Psychiatry 51 269-274, 1990 Jacobsen FM Possible augmentation of antidepressant response by buspirone. J Clin Psychiatry 52 217-220, 1991... 

Non-competitive inhibitors. These inhibitors bind to the enzyme or the enzyme-substrate complex at a site other than the active site. This results in a decrease in the maximum rate of reaction, but the substrate can still bind to the enzyme. An analogous concept is that of allosteric inhibition. The site of binding of an allosteric inhibitor is distinct from the substrate binding site. In this case, the inhibitor is not a steric analog of the substrate and instead binds to the allosteric site (the phenomenon was termed thus by Monod and Jacob). 

The detailed biochemical studies not only confirmed the Jacob-Monod hypothesis, they gave further details about the nature of repressor interaction and a detailed characterization of the repressor binding site. The repressor binds mainly to one side of the double helix, over a 36-base region covered by the symmetry axis. It inhibits expression because it binds to a site that overlaps the polymerase binding site. 

Ruehlmann DO, Steinert JR, Valverde MA, Jacob R, Mann GE. 1998. Environmental estrogenic pollutants induce acute vascular relaxation by inhibiting L-type Ca2 + channels in smooth muscle cells. FASEB J 12 613-619. 

Vitamin B12 can be absorbed when present in physiological amounts only if it is first bound to a specific protein—the so-called intrinsic factor—that tightly binds to the vitamin. The complex then passes through the jejunum to the ileum, which contains receptor sites for the vitamin B12/intrinsic factor complex. Calcium ions are required for the reaction between ileal receptors and the intrinsic factor/vitamin B12 complex. The reaction is inhibited by EDTA and reduced by a pH below 5.4. The vitamin appears to be separated from intrinsic factor at the ileal receptor sites and is then bound to another protein carrier, transcobalamin II, which transports the vitamin and permits its uptake by a number of tissues. The subject has been well reviewed by Jacob and her colleagues (Jl). Removal of 60 cm of ileum may impair vitamin B12 absorption and with the loss of 180 cm absorption is almost always affected. 

Beach CA, Mays DC, GuUer RC, Jacober CH, Gerber N. Inhibition of ehmination of caffeine by disulfiram in normal subjects and recovering alcoholics. Clin Pharmacol Ther 1986 39(3) 265-70. 

Takase O, Minto AW, Puri TS, Cunningham PN, Jacob A, Hayashi M, Quigg RJ. Inhibition of NF-kappaB-dependent Bcl-xL expression by clusterin promotes albumin-induced tubular cell apoptosis. Kidney Int. 2007 Dec 12. 

Chabrier, P. E., Jacob, J. (1980). In vivo and in vitro inhibition of cholinesterase by methyl-1 (S methyl phosphoryl-3) imidazolium (MSPI), a model of an instantly aged phosphorylated enzyme. Archives of Toxicology, 45, 15-20. 

Jacobs MM. 1990. Potassium inhibition of DMH-induced small intestinal tumors in rats. Nutr Cancer 14 95-101. 

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