Walter E. Kyle

Activation of cystathionine synthase by adenosylmethionine and adenosylethionine

Summary The administration of ethionine results in a rapid and marked increase in cystathionine synthase in rat liver. The specific activity doubles within 20 minutes following a dose of 400 mg/kg. Pretreatment with either cycloheximide or actinomycin D fails to prevent this response. Preincubation of crude liver extracts with ethionine, methionine or ATP does not affect the specific activity. However, preincubation with ATP together with either methionine or ethionine leads to a marked increase in cystathionine synthase. This finding is duplicated by the preincubation of partially-purified cystathionine synthase with S-adenosylmethionine.

Methionine metabolism in mammals. Regulation of homocysteine methyltransferases in rat tissue

We studied two mammalian enzymes capable of remethylating homocysteine. Betaine-homocysteine methyltransferase was found only in rat liver while N 5 -methyltetrahydrofolate-homocysteine methyltransferase could be demonstrated in all tissues except small intestinal mucosa. Various hormones significantly affect the specific activity of the enzymes. These effects depend on hormone, enzyme, and tissue. The responses of the two transmethylases to dietary changes differed markedly. Betaine-homocysteine methyltransferase increased with protein and methionine feeding. N 5 -Methyltetrahydrofolate-homocysteine methyltransferase on the other hand increased under conditions that suggested the need for methionine synthesis. We conclude that N 5 -methyltetrahydrofolate-homocysteine methyltransferase activity contributes significantly to the regulation of methionine metabolism in mammals. High protein diets repress the synthesis of this enzyme in liver.

Ethanol-induced changes in methionine metabolism in rat liver

Abstract The administration of alcohol to rats fed a protein-restricted diet results in significant changes in the hepatic content of four enzymes of methionine metabolism. The levels of s-adenosylmethionine synthetase, cystathionine synthase, and betaine-homocysteine methyltransferase increase while the level of methyltetrahydrofolate-homocysteine methyltransferase decreases. These changes represent a reversal of the normal adaptive response to protein-restriction. The resultant impairment in methionine conservation could explain the alcohol-induced increase in the dietary lipotrope requirement.

Methionine metabolism in mammals: Kinetic study of betaine-homocysteine methyltransferase

Abstract We have studied the kinetic properties of betaine-homocysteine methyltransferase prepared from rat liver. The Michaelis constants for the substrates are K hetaine = 48 μm and K homocysteine = 12 μm . The reaction conforms to the Ordered Bi Bi model. Homocysteine is the first substrate to add to the enzyme and N,N -dimethylglycine is the first product released. In addition to the reaction products, l -cysteine and l -cystine also inhibit the enzyme. These effects of methionine and cyst(e)ine on the betaine-chomocysteine methyltransferase may be significant in the regulation of methionine metabolism in the intact animal.

Methionine metabolism in mammals: Regulatory effects of S-adenosylhomocysteine

Abstract S -Adenosylhomocysteine inhibits betaine-homocysteine methyltransferase. The inhibition is nonlinear, competitive in relation to homocysteine, and noncompetitive in relation to betaine. S -Adenosylhomocysteine activates cystathionine synthase at all concentrations of the substrates, serine and homocysteine. By altering the distribution of homocysteine between these competing pathways, S -adenosylhomocysteine may be significant in the regulation of methionine metabolism in the intact animal.

Regulation of the betaine content of rat liver

Abstract The dietary levels of both choline and protein are major determinants of the content of betaine in rat liver. Increased protein intake decreases hepatic betaine. Our studies indicate that an increase in the betaine-homocysteine methyltransferase reaction due to an increased availability of homocysteine is the basis for this effect of dietary protein.

Abnormal methionine adenosyltransferase in hypermethioninemia

Abstract Methionine adenosyltransferase activity was reduced in liver from a child with hypermethioninemia. Kinetic studies demonstrated a pattern suggesting negative cooperativity for enzyme derived from rat and human liver. The patients enzyme was characterized by a decrease in the apparent maximum Km(met). The characteristics of this mutant enzyme could explain the clinical abnormalities.

Methionine metabolism in mammals: regulation of methylenetetrahydrofolate reductase content of rat tissues.

Abstract Methylenetetrahydrofolate reductase was present in all of the 12 rat tissues which we studied. The specific activity of the enzyme was highest in kidney, testes, pancreas, and liver—a pattern similar to that of methyltetrahydrofolate homocysteine methyltransferase. In liver, kidney, brain, and spleen, the specific activity of the reductase declined with age. The protein content of the diet had little effect on the enzyme in liver and brain. Protein restriction resulted in an increased specific activity in kidney and spleen. Treatment with several hormones led to significant and opposite changes in liver and kidney. Hydrocortisone, thyroxine, estradiol, and growth hormone increased the specific activity in liver while decreasing renal levels. Dietary or hormone-induced changes in the activity of methylenetetrahydrofolate reductase did not necessarily parallel the changes in the activity of the homocysteine methyltransferase. Thus it is possible that these exogenous factors may affect the rates of synthesis and of utilization of methyltetrahydrofolate.

Ethanol Effects on Methionine Metabolism in Rat Liver

Summary Ethanol administration, in either chronic feeding or acute experiments, increased the level of methionine-activating enzyme in rat liver. The increase in methionine-activating enzyme did not occur in animals treated with puromycin or actinomycin D. The simultaneous administration of methionine or choline failed to inhibit this effect of ethanol. Prolonged ethanol feeding also led to an increase in hepatic cystathionase while acute intoxication resulted in a balanced increment in cystathionine synthase and betaine-homocysteine methyltransferase. We discussed the possible relationship of these results to the increased lipotrope requirement which attends alcohol consumption in rats.

Enzymes of methionine metabolism in regenerating rat liver.

Abstract Significant changes in the activities of the enzymes of methionine metabolism occur in the regenerating rat liver. We found that the levels of methionine adenosyl-transferase and cystathionine synthase increased immediately after partial hepatectomy. A secondary peak of activity was noted on the eighth postoperative day. In contrast, activities of both 5-methyltetrahydrofolate homocysteine methyltransferase and betaine-homocysteine methyltransferase declined. This pattern of changes suggests that transsulfuration, rather than methionine conservation, is a major metabolic response in hepatic regeneration.