Protein-L-histidine N-pros-methyltransferase (METTL9)

Protein-L-histidine N-pros-methyltransferase (METTL9) is a protein methyltransferase that specifically catalyzes N1-methylation of histidine residues within His-x-His (HxH) motifs, where the intervening “x” is preferably a small amino acid[1][2][3]. METTL9 is a member of the seven-β-strand (7BS) methyltransferase family and uses S-adenosylmethionine (SAM) as a methyl donor, binding SAM/SAH in a deep groove and transferring the methyl group to the N1 position of the imidazole ring of the substrate histidine[1]. It acts on multiple substrates, notably including the mitochondrial electron transport chain subunit NDUFB3 and the immunomodulatory protein S100A9, mediating posttranslational modification across a broad range of cellular and tissue contexts[2]. Methylation by METTL9 has functional consequences such as enhancing Complex I-dependent mitochondrial respiration and reducing zinc binding to certain substrate peptides, thereby regulating both cellular metabolism and signaling pathways[2]. METTL9 accounts for the majority of 1-methylhistidine found in the human and mouse proteomes, with evidence supporting tissue- and organelle-specific roles, including the endoplasmic reticulum and mitochondria[2]. While METTL9 has not yet become a direct drug target, its emerging links to mitochondrial function, cancer, and other fundamental processes make it a molecule of growing biomedical interest[1][2][3].

Other names

METTL9DREVCGI-81DREV1hMETTL9PAP1CTB-31N19.3Methyltransferase-like protein 9DORA reverse strand protein 1p53 activated protein 1

Not applicable: no drugs are currently known to target METTL9 directly. Hypothetically: Inhibition would reduce protein N1-histidine methylation on substrates, potentially impacting mitochondrial function and protein interactions[1][2]