Architectures, mechanisms and molecular evolution of natural product methyltransferases

Abstract

The addition of a methyl moiety to a small chemical is a common transformation in the biosynthesis of natural products across all three domains of life. These methylation reactions are most often catalysed by S-adenosyl-L-methionine (SAM)-dependent methyltransferases (MTs). MTs are categorized based on the electron-rich, methyl accepting atom, usually O, N, C, or S. SAM-dependent natural product MTs (NPMTs) are responsible for the modification of a wide array of structurally distinct substrates, including signalling and host defense compounds, pigments, prosthetic groups, cofactors, cell membrane and cell wall components, and xenobiotics. Most notably, methylation modulates the bioavailability, bioactivity, and reactivity of acceptor molecules, and thus exerts a central role on the functional output of many metabolic pathways. Our current understanding of the structural enzymology of NPMTs groups these phylogenetically diverse enzymes into two MT-superfamily fold classes (class I and class III). Structural biology has also shed light on the catalytic mechanisms and molecular bases for substrate specificity for over fifty NPMTs. These biophysical-based approaches have contributed to our understanding of NPMT evolution, demonstrating how a widespread protein fold evolved to accommodate chemically diverse methyl acceptors and to catalyse disparate mechanisms suited to the physiochemical properties of the target substrates. This evolutionary diversity suggests that NPMTs may serve as starting points for generating new biocatalysts.

Methyltransferase‐Directed Labeling of Biomolecules and its Applications

“…Many AdoMet‐dependent MTases that target natural products (NP MTases) exist and they can generally be categorized based on their preference for oxygen, nitrogen, sulfur, or carbon atoms as their nucleophilic substrates 65. As such, NP MTases participate in the modification of a large numbers of structurally diverse small organic molecules, which affects their bioavailability, activity, and reactivity in processes ranging from metabolism to signaling and biosynthesis 65b. Many NP MTases have been shown to feature a Rossman‐like fold structural motif that is often extended by additional domains.…”

Mechanisms of Arsenic Detoxification and Resistance

“…Methylation modulates the bioavailability, bioactivity and reactivity of acceptor atoms and the most common methyl accepting atoms are C, O, N and S (Liscombe et al, 2012). Addition of methyl group is done enzymatically and requires an activated methyl group.…”

Estudos de biotransformação de pesticidas organofosforados e biometilação de compostos fenólicos por fungos de ambiente marinho

“…158 As enzimas metil transferases mais abundantes são O-dirigidas e conhecidas como orto-metiltransferases (OMTs).…”

“…158,159 Árvores de álamo (Populus sp.) codificam 26 moléculas diferentes de ortometiltransferases, enquanto apenas duas enzimas orto-metiltransferases são encontradas em seres humanos, a enzima catecol orto-metiltransferase (COMT) e N-acetil-serotonina ortometiltransferase (NOMT).…”

“…codificam 26 moléculas diferentes de ortometiltransferases, enquanto apenas duas enzimas orto-metiltransferases são encontradas em seres humanos, a enzima catecol orto-metiltransferase (COMT) e N-acetil-serotonina ortometiltransferase (NOMT). 158 As enzimas metiltransferases podem servir como reguladores, modificando a reatividade de vários xenobióticos tóxicos para seres humanos. O conhecimento das rotas de biodegradação destes compostos tóxicos é de interesse ambiental, uma vez que toneladas de pesticidas organofosforados e compostos fenólicos são lançados no meio ambiente.…”