Methionine inhibition

This functional deficiency of folate is exacerbated by the associated low concentrations of methionine and S-adenosyl methionine, edthough most tissues (apeut from the centred nervous system) edso have beteune-homocysteine methyltransfereise that may be adequate to maintedn tissue pools of methionine. Under normed conditions S-adenosyl methionine inhibits methylene-tetrediydrofolate reductase and prevents the formation of further methyl-tetrediydrofolate. Relief of this inhibition results in increased reduction of one-cetrbon substituted tetrediydrofolates to methyl-tetrahydrofolate. 

A number of studies have shown that natural metabolites can inhibit transamination. With a partially purified mung bean preparation which could use lysine, methionine, or aromatic amino acids as amino donors, it was found that the aliphatic substrates (e.g., lysine and methionine) inhibited the transamination of phenylalanine. The extent of this inhibition was related to their effectiveness as substrates, suggesting that they competed with phenylalanine (Gamborg, 1965). Using the highly purified but multispecific aromatic amino acid (and aspartate) aminotransferase from bush bean. Forest and Wightman (1973) demonstrated that 40 mM aspartate inhibited transamination of L-phenylalanine (40 mM) by 85%. Further experiments showed that elevated concentrations of phenylalanine reduced the inhibition by aspartate double-reciprocal plots indicated competitive inhibition. These... 

Uyeda M, Demain AL. Methionine inhibition of thienamycin formation. ) ind Microbiol 1988 3 57-59. 

When exposed to sunlight, it is converted to a white insoluble resin, disacryl. Oxidized by air to propenoic acid small amounts of hy-droquinone will inhibit this. Bromine forms a dibromide which is converted by barium hydroxide into DL-fructose. The acrid odour of burning fats is due to traces of propenal. It is used in the production of methionine and in controlled polymerization reactions to give acrolein polymers. ... 

In the case of hyperphenylalaninaemia, which occurs ia phenylketonuria because of a congenital absence of phenylalanine hydroxylase, the observed phenylalanine inhibition of proteia synthesis may result from competition between T.-phenylalanine and L-methionine for methionyl-/RNA. Patients sufferiag from maple symp urine disease, an inborn lack of branched chain oxo acid decarboxylase, are mentally retarded unless the condition is treated early enough. It is possible that the high level of branched-chain amino acids inhibits uptake of L-tryptophan and L-tyrosiae iato the brain. Brain iajury of mice within ten days after thek bkth was reported as a result of hypodermic kijections of monosodium glutamate (MSG) (0.5—4 g/kg). However, the FDA concluded that MSG is a safe kigredient, because mice are bom with underdeveloped brains regardless of MSG kijections (106). 

Modulation of second-messenger pathways is also an attractive target upon which to base novel antidepressants. Rolipram [61413-54-5] an antidepressant in the preregistration phase, enhances the effects of noradrenaline though selective inhibition of central phosphodiesterase, an enzyme which degrades cycHc adenosiae monophosphate (cAMP). Modulation of the phosphatidyl iaositol second-messenger system coupled to, for example, 5-HT,, 5-HT,3, or 5-HT2( receptors might also lead to novel antidepressants, as well as to alternatives to lithium for treatment of mania. Novel compounds such as inhibitors of A-adenosyl-methionine or central catechol-0-methyltransferase also warrant attention. 

Similarly, by adding analogs of L-methionine, the methylation of C6 is inhibited, resulting in the formation of 6-demethylchlortetracycline. The analogs that may be used include D-methionine and ethionine. 

Systematic screening experiments have identified more than 100 synthetic compounds with potent antiangiogenic activity. The mode of action for most of these molecules is not well understood, but some of the 40 compounds are well advanced in clinical trials (Table 3). The first substance to have entered clinical trials was the Fumagillin-derivative AGM 1470. Fumagillin is an antibiotic which inhibits bFGF- and PDGF-induced endothelial cell proliferation. The mechanism of action of AGM 1470 is poorly understood, but it was shown that it binds and inhibits the metalloprotease methionine aminopeptidase (MetAp-2). 

Figure 45-14. Homocysteinuria and the folate trap. Vitamin 6,2 deficiency leads to inhibition of methionine synthase activity causing homocysteinuria and the trapping of folate as methyltetrahydrofolate.

Sulphonamides are structural analogues of PABA. They competitively inhibit the incorporation of PABA into dihydropteroic acid and there is some evidence for their incorporation into false folate analogues which inhibit subsequent metabolism. The presence of excess PABA will reverse the inhibitory action of sulphonamides, as will thymine, adenine, guanine and methionine. However, these nutrients are not normally available at the site of infections for which the sulphonamides are used. 

Paracetamol-induced hepatotoxicity can be prevented in animals with SOD, catalase and allopurinol (Kyle et al., 1987 Jaeschke, 1990 Tirmenstein and Nelson, 1990), and by N-acetyl-L-cysteine or methionine in humans (Meredith et al., 1986 Nelson, 1990). The protective efiect of allopurinol in mice only occurred at high concentrations, suggesting that its effect was related to scavenging of ROMs rather than inhibition of their production by XO (Jaeschke, 1990). 

Delta receptors are relatively selective for two related penta-peptides, methionine enkephalin and leucine enkephalin (met- and leu-enkephalin), which were isolated from porcine brain (Hughes 1975). Both met- and leu-enkephalin inhibit electrically induced contractions of guinea pig ileum, an effect that mimics those effects seen with opioid drugs, and is naloxone reversible. The enkephalins are processed posttranslational ly from proenkephalin, and secreted from central and peripheral neurons and endocrine cells in the adrenal medulla. 

The second important issue related to commercial use of desulfurization biocatalysts is their inhibition by sulfate. The sulfur repression mechanism in most Rhodococcus species limits their use or activity in presence of sulfate- and sulfur-containing amino-acids such as cysteine, methionine, etc. To alleviate this problem, expression of the dsz genes under the control of alternate promoters has been investigated. 

Another report describing an approach to achieve alleviation of sulfur repression came from the Matsui research group. The dsz genes were cloned into a strain Rhodococcus sp. strain T09 under the promoter rrn of the strain T09 using a Rhodococcus-E. coli shuttle vector [214,215], This resulted in a strain which desulfurized DBT to 2-HBP in presence of sulfate, cysteine, or methionine. Similar approach was also used by Kurane to construct a gene expressing dszA-D enzymes, which eliminate the sulfate inhibition effects [216],... 

Fig. 14.10 Folate metabolism and role of MTHFR. Genetically reduced MTHFR activity affects the distribution between folate species required for protein and DNA synthesis. Higher availabil ity of 5,10-methylenetetrahydrofolate (CH2THF) potentiates the TS inhibition by 5-FdUMP, the active metabolite of 5-FU. Hey, homocysteine Met, methionine CH3HF, 5-methyltetrahydrofolate TS, thymidylate synthase 5-FdUMP, fluorodeoxyuridine monophosphate.

Gintzler AR, Xu H. Different G proteins mediate the opioid inhibition or enhancement of evoked methionine] enkephalin release. Proc Natl Acad Sci USA 1991 88 4741-4745. 

---