Sterol 24-C-methyltransferase (SMT) (SMT)

Sterol 24-C-methyltransferase (SMT) is an essential enzyme in the ergosterol biosynthetic pathway of Leishmania parasites, where it catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to the C-24 position of sterol precursors (Magaraci et al., 2003; Kumari & Singh, 2025). This methylation is a defining step that distinguishes the synthesis of ergosterol in parasites and fungi from the synthesis of cholesterol in humans, who lack a functional SMT ortholog (Kumari & Singh, 2025; Kwofie et al., 2021). Ergosterol is a vital component of the parasite's cell membrane, playing a crucial role in maintaining membrane fluidity, structural integrity, and the proper functioning of membrane-bound proteins and the mitochondria (Mukherjee et al., 2019; Kwofie et al., 2021). Inhibition of SMT by compounds such as azasterols leads to the depletion of ergosterol and the accumulation of abnormal sterol intermediates, which compromises the parasite's viability and virulence (Magaraci et al., 2003; Gros et al., 2006). Consequently, SMT is considered a highly selective and validated therapeutic target for the treatment of various forms of leishmaniasis (Kumari & Singh, 2025). Additionally, mutations in the SMT gene have been linked to resistance against existing antileishmanial drugs like amphotericin B, further underscoring its biological significance (J Biomol Struct Dyn, 2024).

Other names

Sterol 24-methyltransferaseDelta(24)-sterol methyltransferaseS-adenosyl-L-methionine:C-24-Delta-sterol-methyltransferaseERG624-SMTSterol C-24 methyltransferase

Inhibition of sterol 24-C-methyltransferase prevents the methylation of sterol precursors at the C-24 position, a critical step in ergosterol biosynthesis. This leads to the depletion of ergosterol and the accumulation of abnormal, non-alkylated sterols, which disrupts cell membrane integrity, increases membrane fluidity, and impairs mitochondrial function, ultimately leading to parasite cell death.