MetAP1

Methionine aminopeptidase 1 (MetAP1) catalyzes the excision of N-terminal initiator methionine (iMet) from nascent peptide chains, a critical step for proper protein maturation and post-translational modification^[1][2]. Mechanistically, MetAP1 coordinates with the nascent polypeptide-associated complex and N-terminal acetyltransferase D (NatD) to cotranslationally process histones H2A and H4, ensuring chromatin integrity during S-phase^[3]. Compared with the related isoform MetAP2, MetAP1 exhibits higher specificity toward N termini starting with Met-Ser, Met-Pro, and Met-Ala, which MetAP2 cannot efficiently process, highlighting non-redundant substrate preferences^[1][4]. In disease models, elevated METAP1 expression in endothelial cells contributes to impaired angiogenesis and proinflammatory signaling, notably observed in preeclampsia^[5]. Experimental models using METAP1 knockout or knockdown in human cell lines reveal slowed G2/M cell cycle progression and reduced proliferation, confirming its essential role in cell division^[2][4]. Structurally, MetAP1 contains cytosolic and mitochondrial variants with distinct active-site conformations that accommodate specific substrates, differentiating it from MetAP2 and the mitochondrial MetAP1D isoform^[6][7]. For research applications, selective MetAP1 inhibitors, including pyridinylquinazolines and bengamide derivatives, effectively target enzymatic activity in vitro and in primary cells, enabling mechanistic studies and potential therapeutic exploration^[8][9]. These inhibitors demonstrate utility in probing MetAP1-dependent cell cycle regulation and protein N-terminal processing, offering precise tools for functional and pharmacological analyses^[2][9].