Biotechnological applications of S-adenosyl-methionine-dependent methyltransferases for natural products biosynthesis and diversification

Zhang, Congqiang; Sultan, Stella Amelia; T, Rehka; Chen, Xixian

doi:10.1186/s40643-021-00425-y

Bioresources and Bioprocessing

Table 1 Summary of recently discovered methyltransferases

From: Biotechnological applications of S-adenosyl-methionine-dependent methyltransferases for natural products biosynthesis and diversification

Product	Enzyme	Name	Reaction type	Natural host	Gene cluster/biosynthetic pathway	Discovery method	Promiscuity	Refs.
Novel methyltransferases discovery
Nonamycin I	NcmP	Carboxylate O-methyltransferase	Methylation	Saccharothrix syringae NRRL B-16468	Tetramic acid, nocamycin biosynthetic cluster	Biosynthetic gene cluster identification. mutant strain with NcmP disruption by λ-RED recombination	Specific methylation site, methylate the pathway intermediates	Mo et al. (2017)
Antibiotic CC1065	C10P	Raidcal SAM enzyme	Radical generation and methylation	Shewanella woodyi ATCC 51908	Spirocyclopropylcyclohexadienone biosynthesis cluster	Benzodipyrrole Biosynthetic gene cluster identification. Gene inactivation and re-introduce the same gene, and intermediate characterization	N.A	Jin et al. (2018)
Antibiotic CC1065	C10Q	Methyltransferase	Methylation and cyclization	S. Zelensis nrrl 11183	Spirocyclopropylcyclohexadienone biosynthesis cluster		N.A	Jin et al. (2018)
Xantholipin	XanM1	O-methyltransferase	Methylation	Streptomyces flavogriseus	Aromatic polyketides, Polycyclic xanthones biosynthetic cluster	Biosynthetic gene cluster identification. In vivo gene deletion study	N.A	Kong et al. (2020)
	XanM2	O-methyltransferase	Methylation				Specific methylation site, methylate the pathway intermediates
	XanM3	O-methyltransferase	Methylation
Gentamicin C	GenN	N-methyltransferase	Methylation	Micromonospora echinospora	Aminoglycosides, Gentamicin C biosynthesis cluster	Biosynthetic cluster identification. Systematic deletion of the methyltransferase genes. knockout the biosynthetic gene cluster and complement with plasmids containing the MT genes one by one and perform in vivo biotransformation	Specific methylation site, methylate the pathway intermediates	Li et al. (2018)
	GenD1	C-methyltransferase	Methylation
	GenK	C-methyltransferase	Methylation
	GenL	Terminal 6′-N-methyltransferase	Methylation		Outside the gentamicin C biosynthetic cluster	Genome sequencing. BLAST search. Enzyme screening to identify genL. Gene deletion to confirm in vivo activity. In vitro enzyme characterization
Pre-sodorifen pyrophosphate	SodC	C-methyltransferase	Methylation and cyclization	Serratia plymuthica WS3236	Sodorifen biosynthetic gene cluster	Genome sequencing. In silico methods (antiSMASH and ClusterFinder) to identify the biosynthetic gene cluster. Overexpress the gene cluster in E. coli	N.A	Duell et al. (2019)
C6,C7 prenyl pyrophosphate	IPPMT	Isoprenyl pyrophosphate methyltransferase	Methylation	Streptomyces monomycini	Terpenoids biosynthetic cluster	BLAST GPPMT with genome sequences of S. monomycini. Overexpression and purification from E. coli for activity characterization	Multiple methylation	Drummond et al. (2019)
Teleocidin B	TleD	C-methyltransferase	Methylation and cyclization	Streptomyces mediocidicus	Indole alkaloid, Teleocidin B biosynthesis cluster	BLAST search to identify teleocidin B biosynthesis cluster. overexpress the gene cluster in Streptomyces lividans TK21	Produce a mixture of isomers	Awakawa et al. (2014)
Promiscuous methyltransferase applications
Vanillin	COMT	Caffeic acid O-methyltransferase	Methylation	Homo sapiens	Escherichia coli	Natural substrate is caffeic acid		Kunjapur et al. (2016)
Pterostilbene	COMT	Caffeic acid O-methyltransferase	Methylation	Arabidopsis thaliana	Escherichia coli	Natural substrate is caffeic acid		Heo et al. (2017)
Fatty acid methyl esters	DmJHAMT	Juvenile hormone acid O-methyltransferase	Methylation	Drosophila melanogaster	Juvenile hormone biosynthesis	Homolog, sequence alignment	Broad specificity for medium chain free fatty acids	Sherkhanov et al. (2016)

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