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Title

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

AuthorsPérez-Miguelsanz, Juliana; Vallecillo, Néstor; Garrido, Francisco ; Reytor, Edel ; Pérez-Sala, Dolores ; Pajares, María A.
KeywordsBetaine homocysteine methyltransferase
One-carbon metabolism
Cytosolic retention
Galactosamine intoxication
Oxidative stress
Subcellular localization
Issue Date2017
PublisherElsevier
CitationBBA - Biochimica et Biophysica Acta 1864(7): 1165-1182 (2017)
AbstractThe 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.
Publisher version (URL)https://doi.org/10.1016/j.bbamcr.2017.03.004
URIhttp://hdl.handle.net/10261/146910
DOI10.1016/j.bbamcr.2017.03.004
ISSN0006-3002
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(IIBM) Artículos
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