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

Juliana Pérez-Miguelsanz, Néstor Vallecillo, Francisco Garrido, Edel Reytor, Dolores Pérez-Sala, María A. Pajares
  • Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, March 2017, Elsevier
  • DOI: 10.1016/j.bbamcr.2017.03.004

What is it about?

Betaine homocysteine methyltransferase locates both to the cytoplasm and the cell nucleus. During acute liver injury BHMT accumulates in the nucleus while reducing its levels in the cytoplasm. This change of subcellular localization is due to the reduced GSH/GSSG ratio in treated cells (D-galactosamine, paracetamol/acetaminophen, buthionine sulfoximine) and addition of N-acetylcysteine prevents this anomalous distribution. Moreover, basic residues in the N-terminal of BHMT are involved in the regulation of subcellular localization. Nuclear BHMT is an active homotetramer in normal and galactosamine treated livers, but not in paracetamol-treated livers. Changes in nuclear BHMT activity correlate with the global protein homocysteinylation detected in this compartment, thus supporting the role of nuclear BHMT in the remethylation of homocysteine.

Why is it important?

This is the first report on homocysteine remethylation in the nucleus, further supporting the existence of a nuclear branch of the methionine cycle that supports epigenetic modifications.


Dr María A Pajares
Instituto de Investigaciones Biomedicas Alberto Sols

Although we cannot exclude a putative moonlighting activity of BHMT in the nucleus, all our date support that there is a nuclear branch of the methionine cycle in charged of: 1) providing S-adenosylmethionine to specific epigenetic modifications ; 2) removing the S-adenosylhomocysteine generated by these methylation reactions; and 3) remethylating homocysteine to maintain nuclear methionine levels. The nuclear accumulation of enzymes of the cycle upon an hepatic injury suggests the need to increase the function of the pathway to support the required modifications that allow survival or cell death.

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The following have contributed to this page: Dr María A Pajares