Development of methyltransferase activities of human fetal tissues.

Abstract

Extract: N5-Methyltetrahydrofolate-homocysteine methyltransferase specific activity was higher in fetal (2nd trimester) human liver and kidney (4.70 ± 0.20 and 7.25 ± 0.23 nmol/mg protein/hr) than in mature human liver and kidney (1.30 ± 0.16 and 0.76 ± 0.18 nmol/mg protein/hr). During the same period, there was a significant correlation of decreasing specific activity of this enzyme in fetal brain with increasing crown-rump length (r = −0.72; P < 0.005), reaching the specific enzymatic activity of adult brain (1.37 ± 0.26 nmol/mg protein/hr). Betaine-homocysteine methyltransferase specific activity was lower in fetal liver and brain (1.82 ± 0.21 and 0.20 ± 0.05 nmol/mg protein/hr) than in mature liver and brain (7.78 ± 1.89 and 0.37 ± 0.07 nmol/mg protein/hr). During the same period, there was a significant correlation of increasing enzymatic activity in fetal kidney with increasing crown-rump length (r = 0.80; P < 0.005) toward the mean specific activity of mature kidney (22.6 ± 2.0 nmol/mg protein/hr). Serine tetrahydrofolate 5,10-hydroxymethyltransferase specific activity showed no significant difference between fetal and mature liver and kidney; however, the fetal brain showed a significant correlation of decreasing specific activity of this enzyme with increasing crown-rump length (r = −0.69; P < 0.005). The specific activities of betaine-homocysteine methyltransferase and serine-tetra-hydrofolate 5,10-hydroxymethyltransferase in the liver of the neonate was not different from that in the mature liver. N5-Methyltetrahydrofolate-homocysteine methyltransferase in neonatal liver attained a specific activity similar to that found in mature liver before cystathionase did. Cystathionase in 2nd trimester human fetal kidney, in contrast to cystathionase in human fetal liver and brain, already has attained two-thirds of the mean specific activity of mature kidney. Speculation: Although the measurements of these enzyme activities as assayed in vitro do not take into consideration substrate availability in vivo, the relative specific activities of these methyltransferases in human fetal liver and brain, considered together with the absence of cystathionase, suggests to us that perhaps, in these two organs, the trans-sulfuration pathway for the further metabolism of homocysteine is turned off in favor of the N6-methyltetrahydrofolate-Bi2remethylation pathway (Fig. 1). The latter pathway converts 7V6-methyl tetrahydrofolate, the major monoglutamic folate in liver and serum [1], to tetrahydrofolate. The latter form of folate reacts with the f3 carbon of serine, on serine-tetrahydrofolate 5,10 hydroxymethyltransferase, to form Ni · 10-methylenetetrahydrofolate, a 1-carbon precursor for the de novo synthesis of thymidylate, which is uniquely required for DNA but not for RNA. This suggests that the /3 carbon of serine is being shunted into DNA synthesis during periods of rapid cellular multiplication, rather than having the entire carbon skeleton accept the sulfur from homocysteine to form cysteine. The latter thus becomes an essential amino acid in human fetal liver and brain.