Trends in Biochemical Sciences
Many paths to methyltransfer: a chronicle of convergence
Section snippets
In the beginning, a MTase was a MTase was a MTase
Starting with the M.HhaI DNA-MTase structure in 1993 [4], a continuing string of structures for AdoMet-dependent MTases have been reported. These structures are remarkably similar, comprising a seven-stranded β sheet with a central topological switch-point and a characteristic reversed β hairpin at the carboxyl end of the sheet (6↑ 7↓ 5↑ 4↑ 1↑ 2↑ 3↑; Fig. 1a). This sheet is flanked by α helices to form a doubly wound open αβα sandwich, and is henceforth referred to as the Class I MTase
A lesson in cobalamin
As early as 1996, there was a hint that not all AdoMet-dependent MTases would follow the same structural theme. The Escherichia coli cobalamin (vitamin B12)-dependent methionine synthase, MetH, generates methionine from homocysteine, transferring a methyl group from a folate derivative to the bound cobalamin and thence to homocysteine. Periodically, the B12 cobalt is oxidized to a dead-end form, and reactivation requires reductive methylation using AdoMet, flavodoxin and an additional
Knotty new MTase structures SET to SPOUT
This past year has provided two more disparate MTase structures. The SPOUT family of RNA MTases provides the only known cases of Class IV structure 24, 25, 26. These enzymes are unique in three ways: (1) they include a six-stranded parallel β sheet flanked by seven α helices, of which the first three strands form half of a Rossman fold (Fig. 1d); (2) their active site is located near the subunit interface of a homodimer, and might encompass residues extending from both subunits; and (3) the
Conformations of AdoMet and AdoHcy
The bound AdoMet or AdoHcy ligand exhibits significantly different conformations in the five structural classes, which emphasizes its flexibility. Figure 3a compares the prototypical AdoMet and AdoHcy conformations of each structural class by aligning the molecules via their ribose moieties. The ribose ring of AdoMet in Class I adopts an envelope 2′-endo conformation, with its base in the anti position at ∼135° (defined by the O4′–C1′–N9–C4 dihedral; Fig. 3b). The ribose rings of the other
A diverse set of mechanisms for a conserved class of MTase
Substrate-bound complexes have been determined mainly for Class I structures, although recently a Class V (SET) MTase in complex with a lysine-containing peptide has also been determined [36]. All MTases are thought to proceed with direct transfer of the methyl group to substrate with inversion of symmetry in an SN2-like mechanism 37, 38. This reaction also requires that a proton be removed before, concurrent with, or after methyl transfer. Even within the structurally conserved family of Class
Concluding remarks
Evolution has independently achieved AdoMet-dependent MTase activity at least five times, producing five unique structural MTase classes. Most of the other examples of analogous enzyme families also use substrates, such as ATP or NAD, that include a nucleotide ‘handle’ for binding. The Class I and Class IV MTases are plausibly derived from Rossmann-fold proteins, and even the Class III CbiF structure contains a GxGxG nucleotide-binding motif, but uses it unconventionally. The Class II and Class
Acknowledgments
We thank Osnat Herzberg and Steve Gamblin for early release of coordinates. H.L.S. was supported by grants from NIH (GM56775 and DK02794), R.M.B. was supported by a grant from the U.S. National Science Foundation (MCB-9904523), and X.C. was supported by NIH (GM49245 and GM61355) and the Georgia Research Alliance.
References (55)
Purification and characterization of a novel methyltransferase responsible for biosynthesis of halomethanes and methanethiol in Brassica oleracea
J. Biol. Chem.
(1995)Crystal structure of the HhaI DNA methyltransferase complexed with S-adenosyl-l-methionine
Cell
(1993)- et al.
SAM (dependent) I AM: the S-adenosylmethionine dependent methyltransferase fold
Curr. Opin. Struct. Biol.
(2002) - et al.
Catalytic promiscuity and the evolution of new enzymatic activities
Chem. Biol.
(1999) Emergence of diverse biochemical activities in evolutionarily conserved structural scaffolds of proteins
Curr. Opin. Chem. Biol.
(2003)Sequence and structure classification of kinases
J. Mol. Biol.
(2002)Mechanisms for auto-inhibition and forced product release in glycine N-methyltransferase: crystal structures of wild-type, mutant R175K and S-adenosylhomocysteine-bound R175K enzymes
J. Mol. Biol.
(2000)Crystal structure of protein isoaspartyl methyltransferase: a catalyst for protein repair
Structure
(2000)HhaI methyltransferase flips its target base out of the DNA helix
Cell
(1994)The structure of the C-terminal domain of methionine synthase: presenting S-adenosylmethionine for reductive methylation of B12
Structure
(1996)
The structure of the RlmB 23S rRNA methyltransferase reveals a new methyltransferase fold with a unique knot
Structure
Structure of the neurospora SET domain protein DIM-5, a histone H3 lysine methyltransferase
Cell
Structure and catalytic mechanism of a SET domain protein methyltransferase
Cell
Crystal structure and functional analysis of the histone methyltransferase SET7/9
Cell
Structures of SET domain proteins: protein lysine methyltransferases make their mark
Cell
Stereochemical course of the transmethylation catalyzed by catechol O-methyltransferase
J. Biol. Chem.
Structure-guided analysis reveals nine sequence motifs conserved among DNA amino-methyltransferases, and suggests a catalytic mechanism for these enzymes
J. Mol. Biol.
Getting the adrenaline going: crystal structure of the adrenaline-synthesizing enzyme PNMT
Structure
Kinetic and catalytic mechanism of HhaI methyltransferase
J. Biol. Chem.
Crystal structure of the chemotaxis receptor methyltransferase CheR suggests a conserved structural motif for binding S-adenosylmethionine
Structure
Regioselectivity of catechol O-methyltransferase. The effect of pH on the site of O-methylation of fluorinated norepinephrines
J. Biol. Chem.
Crystal structure of a protein repair methyltransferase from Pyrococcus furiosus with its l-isoaspartyl peptide substrate
J. Mol. Biol.
The crystal structure of MT0146/CbiT suggests that the putative precorrin-8w decarboxylase is a methyltransferase
Structure
Structure of the catalytic domain of human DOT1L, a non-SET domain nucleosomal histone methyltransferase
Cell
Biological methylation: selected aspects
Annu. Rev. Biochem.
Purification and characterization of a monohalomethane-producing enzyme S-adenosyl-l-methionine: halide ion methyltransferase from a marine microalga, Pavlova pinguis
Biosci. Biotechnol. Biochem.
Analogous enzymes: independent inventions in enzyme evolution
Genome Res.
Cited by (731)
An optimized purification protocol for enzymatically synthesized S-adenosyl-L-methionine (SAM) for applications in solution state infrared spectroscopic studies
2024, Spectrochimica Acta - Part A: Molecular and Biomolecular SpectroscopyKMT2C and KMT2D aberrations in breast cancer
2024, Trends in CancerStructure of methyltransferase RedM that forms the dimethylpyrrolinium of the bisindole reductasporine
2024, Journal of Biological ChemistryFunctional characterization of a naphthalene-O-methyltransferase from Nocardia sp. CS682
2024, Enzyme and Microbial TechnologyStructural and computational insights into the regioselectivity of SpnK involved in rhamnose methylation of spinosyn
2023, International Journal of Biological MacromoleculestRNA m<sup>1</sup>G9 modification depends on substrate-specific RNA conformational changes induced by the methyltransferase Trm10
2023, Journal of Biological Chemistry