Transamination inhibition

PEP carboxylase occurs in yeast, bacteria, and higher plants, but not in animals. The enzyme is specifically inhibited by aspartate, which is produced by transamination of oxaloacetate. Thus, organisms utilizing this enzyme control aspartate production by regulation of PEP carboxylase. Malic enzyme is found in the cytosol or mitochondria of many animal and plant ceils and is an NADPIT-dependent enzyme. 

Transamination of barbiturate derivatives with semicarbazide Hydrolysis and acyl migration of corticosteroid esters Rate enhancement by CTABr depends on substrate structure Substrate micellization inhibits hydrolysis and acyl migration Reddy and Katiyar, 1981 Anderson el ai, 1983... 

From a practical viewpoint they suffer from serious product inhibition and/or equilibrium constraints. One way of avoiding the latter issue is to couple the transamination step to a second enzymatic step which removes the coproduct In the example shown in Scheme 6.16 acetophenone undergoes TA-catalyzed transamination using L-alanine as the amine donor. The unfavorable equilibrium and... 

In addition to pulmonary toxicity, nausea/vomiting, lactic acidosis and transaminitis, UCN-01 induced insulin resistance during Phase I clinical trials. As shown recently with rat adipose cells, this effect may be due to UCN-01 inhibition of PKB Thr-308 phosphorylation—no effect on Ser-473 was observed in this study—and subsequent blockade of GLUT4 translocation in response to insulin [104]. If this mode of action is confirmed in the ongoing clinical trials and contrary to what was observed in the PDKl hypomorphic mice (vide supra) [100], insulin resistance may represent an important hurdle in the development of PDKl inhibitors and, in general, of any agent that blocks the PI3K/PKB pathway in adipose and muscle cells. 

GABA synthesis inhibitors act on the enzymes involved in the decarboxylation and transamination of GABA. Glutamic acid decarboxylase (GAD), the first enzyme in GABA biosynthesis, is inhibited easily by carbonyl reagents such as hydrazines [e.g., hydrazinopropionic acid (4.164) or isonicotinic acid hydrazide (4.165)], which trap pyridoxal, the essential cofactor of the enzyme. A more specific inhibitor is allylglycine (4.166). All of these compounds cause seizures and convulsions because they decrease the concentration of GABA. 

Zabinski, R.F., and Toney, M.D. 2001. Metal ion inhibition of nonenzymatic pyridoxal phosphate catalyzed decarboxylation and transamination. J.Am. Chem. Soc. 123 193-198. 

We end this section on enzyme inhibition with a case study about 4-hydroxyphenyl-pyruvate dioxygenase (HPPD) and disorders in tyrosine catabolism. After transamination of tyrosine, 4-hydroxyphenylpyruvate (148) is formed which is then decarboxylated, isomerized and oxygenated by HPPD to yield homogentisate (149) or by hydroxyman-delate synthase (HMS) to yield p-hydroxymandelate (150). 149 serves as the precursor for plastoquinones and tocopherols in plants . Thus, inhibitors of HPPD have been designed... 

The most outstanding effect of rrans-2-phenylcyclopropylamine (5) (generic names tranylcypromine, transamine) is the inhibition of monoamine oxidase (MAO) ... 

PEP is carboxylated to oxaloacetate, transaminated to aspartate ar d shunted into the bundle sheath. Aspartate then is transaminated back to oxaloacetate in the mesophyll, reduced to malate by NADH and decarboxylated to pyruvate by NAD-linked malic enzyme in the bundle-sheath mitochondria. There is no net production of NAD(P)H so the chloroplasts have PSII and may be less effective at inhibiting photorespiration. Pyruvate is phosphorylated in the mesophyll back to PEP, using 2 ATP (Fig. 13.18). 

In vitro studies have been conducted to determine the effect of estrogens on kynurenine aminotransferase, which catalyzes the B(,-dependent transamination of kynurenine to ky-nurenic acid. Some estrogen conjugates (e.g.. c.stradiol disulfate and diethylstilbestrol sulfate) interfere with this transamination, apparently hy reversible inhibition of the aminotransfera.se apoenzyme. Apparently, the estrogen sulfate competes with pyridoxal S-phosphate for interaction with the apoenzyme. In conuast. free estradiol and estrone do not pos.sess this inhibitory property. 

Indolmydn.—Previous evidence on the biosynthesis of indolmycin (88) in Strepto-myces griseus cultures accords with the pathway shown in Scheme 4. The first two steps in the pathway have been carried out using cell-free extracts of 5. griseus - and recent work has led to the isolation of two enzymes which can effect these transformations. The first, tryptophan transaminase, catalysed the pyridoxal phosphate-dependent transamination of L-tryptophan, but not D-trptophan, and in common with some other microbial transaminases, a-ketoglutarate was an efficient amino-group acceptor. L-Phenylalanine, tyrosine, and 3-methyltryptophan (this compound inhibited enzyme function) also underwent transamination. 

The blood alanine level is also always increased, sometimes markedly to about 2-4 times the normal value (L3, L6). This is presumably because the normal transamination of alanine to pyruvate, which requires a-ketoglutarate, is inhibited both by the excess of glutamine in the blood and by the drain on a-ketoglutarate. One other amino acid, camosine, has been found to be present in the plasma or in raised amounts in the urine, in those cases of hyperammonemia where it has been sought (LIO). There are no consistent changes in any of the other amino acids, including lysine, in the blood. 

L-Dopa elimination is primarily by decarboxylation to dopamine. Additional pathways are by 3-O-methylation and transamination. With adequate decarboxylase inhibition, increased amounts of L-dopa are metabolized by the other pathways. The elimination half-life of L-dopa is about 1 hour, and this is extended to about U/2 hours with the addition of carbidopa. 30MD has a half-life of about 15 hours and accumulates with chronic dosing. 

B. Excess phenylalanine inhibits tyrosinase the first step toward melanin production, thus resulting in hypopigmentation. Excess melanin leads to hyperpigmentation. Melatonin is a hormone involved in the sleep cycle. Excessive stimulation of tyrosinase would lead to more melanin and therefore hyperpigmentation. Para-hydroxyphenylpyruvate means less transamination and perhaps more tyrosine converted to melanin and hyperpigmentation. 

---