Betaine homocysteine S-methyltransferase emerges as a new player of the nuclear methionine cycle

Abstract

The paradigm of a cytoplasmic methionine cycle synthesizing/eliminating metabolites that are transported into/out of the nucleus as required has been challenged by detection of significant nuclear levels of several enzymes of this pathway. Here, we show betaine homocysteine S-methyltransferase (BHMT), an enzyme that exerts a dual function in maintenance of methionine levels and osmoregulation, as a new component of the nuclear branch of the cycle. In most tissues, low expression of Bhmt coincides with a preferential nuclear localization of the protein. Conversely, the liver, with very high Bhmt expression levels, presents a main cytoplasmic localization. Nuclear BHMT is an active homotetramer in normal liver, although the total enzyme activity in this fraction is markedly lower than in the cytosol. N-terminal basic residues play a role in cytoplasmic retention and the ratio of glutathione species regulates nucleocytoplasmic distribution. The oxidative stress associated with d-galactosamine (Gal) or buthionine sulfoximine (BSO) treatments induces BHMT nuclear translocation, an effect that is prevented by administration of N-acetylcysteine (NAC) and glutathione ethyl ester (EGSH), respectively. Unexpectedly, the hepatic nuclear accumulation induced by Gal associates with reduced nuclear BHMT activity and a trend towards increased protein homocysteinylation. Overall, our results support the involvement of BHMT in nuclear homocysteine remethylation, although moonlighting roles unrelated to its enzymatic activity in this compartment cannot be excluded.

PDRG1at the interface between intermediary metabolism and oncogenesis

“…The cytoplasmic methionine cycle involves the following (Figure 1 ): (1) methionine adenosyltransferases (MATs) that synthesize AdoMet; (2) a large number of methyltransferases, which methylate many types of substrates, also rendering S-adenosylhomocysteine (AdoHcy); (3) AdoHcy hydrolase (AHCY), which eliminates AdoHcy leading to adenosine and homocysteine (Hcy); and (4) betaine homocysteine S-methyltransferases (BHMT and BHMT2) and methionine synthase (MTR), which methylate Hcy to obtain methionine using betaine or S-methylmethionine and 5-methyltetrahydrofolate, respectively[ 17 , 18 ]. In contrast, the nuclear branch of the pathway involves a more reduced set of enzymes as follows (Figure 1 ): (1) MATs; (2) methyltransferases such as those involved in DNA and histone methylations, GNMT and GAMT; (3) AHCY[ 12 , 13 , 15 , 16 ]; and (4) BHMT[ 19 ]. Of note, levels of MATs, GNMT and AHCY are markedly higher in the cytoplasm than in the nucleus, but increases in the latter compartment can be observed as a consequence of pathological changes in glutathione concentrations and, precisely, decreases in the GSH/GSSG ratio[ 14 ].…”

Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to metabolic stress

“…APOA4 was stimulated by inflammation through activation of TNFR2 and NF-kB signaling in kidney tubular cells (Lee et al, 2017). BHMT remethylates homocysteine to methionine using betaine and contributes to methionine, homocysteine, S-adenosylmethionine, and glutathione homeostasis (Perez-Miguelsanz et al, 2017). In hepatocytes, BHMT upregulation prevent ER stress response, lipid accumulation, and cell death (Ji et al, 2007;Ji et al, 2008).…”

The effects of acutely and subchronically applied DL-methionine on plasma oxidative stress markers and activity of acetylcholinesterase in rat cardiac tissue

“…Some authors suggest that cysteine is the one that causes oxidative stress, and has a higher vascular toxicity than Hcy 8 . Others assume that Hcy masks harmful effects of other substances, such as S-adenosylhomocysteine, formed from excess of Hcy, which inhibits methyltransferase and methylenetetrahydrofolate reductase with subsequent deleterious effects 9 .…”