Effect of Zinc Deficiency on Methionine Metabolism, Methylation Reactions and Protein Synthesis in Isolated Perfused Rat Liver

Abstract

A perfusion technique was utilized to assess the rate of absorption and metabolism of L-methionine by livers isolated from rats fed a diet deficient in zinc. The endogenous concentration of S-adenosyl-L-methionine in the livers from the zinc-deficient rats was near normal, while the concentration in pair-fed controls was approximately 50% of that found in normal livers (ad libitum fed). The rate of uptake of methionine by the livers isolated from zinc-deficient rats was significantly less than in the pair-fed or ad libitum-fed controls. The synthesis of L-methionine, S-adenosyl-L-homocysteine and S-adenosylmethionine was not impaired in the livers from the zinc-deficient rats. However, the methyl group of the S-adenosylmethionine turned over much more slowly in the livers from zinc-deficient rats than in either control group. This was reflected in the depressed rates of methylation of various macromolecules, particularly DNA and histones. The synthesis of nuclear proteins (histones and nonhistone chromosomal proteins) was depressed in the livers from zinc-deficient rats. The reduced synthesis of chromosomal proteins and marked reduction in DNA methylation would be consistent with the finding that DNA biosynthesis and cellular proliferation are markedly depressed in zinc-deficient animals.

Zinc deficiency or excess within the physiological range increases genome instability and cytotoxicity, respectively, in human oral keratinocyte cells

“…There are very few studies that have investigated the relationship between Zn and hypomethylation. However, in one of the previous studies, Zn deficiency was found to reduce the utilisation of methyl groups from SAM in rat liver, resulting in genomic DNA hypomethylation and histone hypomethylation (Duerre and Wallwork 1986;Wallwork and Duerre 1985). This could lead to an increase in MN formation in Zn-depleted cells, as observed in the present study due to whole chromosome loss and malsegregation caused by altered structure of pericentromeric DNA and failure of kinetechore assembly at centromeres ).…”

Does promoter methylation of the SLC30A5 (ZnT5) zinc transporter gene contribute to the ageing-related decline in zinc status?

“…Rats fed Zn-deficient diets have markedly decreased liver DNA methylation status (47) . The methionine cycle, key in the production of the universal methyl donor S-adenosylmethionine, is sensitive to a number of micronutrient deficiencies including Zn (48) .…”

Elevated S-Adenosylhomocysteine Alters Adipocyte Functionality With Corresponding Changes in Gene Expression and Associated Epigenetic Marks

“…The principal metabolic role of micronutrients such as folate is to generate the one-carbon cycle intermediate and universal methyl donor SAM. Not surprisingly, more direct disruption of nutrient-dependent SAM-derived methyl group generation also results in hypomethylation of genomic DNA (40). However, changes in "global" genomic methylation do not necessarily translate to altered promoter methylation states at specific loci (41,42), demonstrating that the mechanisms underlying DNA methylation are tightly directed and regulated rather than passive.…”