Table 1.

Amino acid residue-specific modifying enzymes mentioned in this Review and their native functions. Nonnative substrates and downstream bioorthogonal reactions are mentioned in detail in the text and figures.

Amino acid residue	Modifying Enzyme	Native function
Ala	N/A	N/A
Arg	protein Arg methyltransferases	mono- and dimethylation of the guanidino group
	2-oxoglutarate oxygenases YcfD	oxidation of the Arg Cβ carbon
Asp/Asn	peptide Asp ligases/Asn endopeptidases	ligation and/or hydroylsis of Asp/Asn-containing peptides, some catalyze macrocyclization
Cys	farnesyltransferases/geranylgeranyltransferases	transfer of farnesyl/geranylgeranyl group to Cys
	formyl-generating enzymes	converts Cys thiol group to formaldehyde
	cyclodehydratases YcaO family	cyclodehydration and formation of thiazoline ring
	LanM enzymes	formation of thioether link with dehydrated Ser/Thr
Glu	N/A	N/A
Gln	transglutaminases	ligation with Lys-containing peptides or compounds with primary amines conversion of Gln to Glu
Gly	N-myristoyltransferases	transfer of myristoyl group to the N-terminus of Gly
	sortase A	hydroylsis and ligation of peptides containing Thr-Gly
His	2-oxoglutarate oxygenases (NO66 and MINA53)	hydroxylation of the His Cβ carbon
	LimF prenyltransferase	C-prenylation of the imidazole ring
Ile	N/A	N/A
Leu	α-ketoglutarate dioxygenase, Mur15	Cβ-hydroxylation of Leu in muraymycins-type peptides
Lys	transglutaminases	ligation with Gln-containing peptides
	N-myristoyltransferases	transfer of myristoyl group to the ε-NH2 of Lys at the N-terminus
	Lys acyltransferases	transfer of acetyl group to the Lys ε-NH2
	Lys methyltransferases	transfer of methyl to the Lys ε-NH2
	biotin ligase	transfer of biotin to the Lys ε-NH2
	lipoic acid ligases LplA	transfer of lipoyl group to the Lys ε-NH2
Met	Met aminopeptidases	cleavage of the Met at N-terminus of peptides
Phe	N/A	N/A
Pro	tyrosinase abTyr	attaches Tyr to N-Pro and oxidizes it to O-quinones
Ser	formyl-generating enzymes	converts Ser side chain to formaldehyde
Ser/Thr	O-linked N-acetylglucosamine transferase	transfers Glc-NAc to OH side chain
	prenyltransferase TolF	transfers prenyl group to OH side chain
	cyclodehydratases YcaO	forms oxazoline and methyloxazoline rings
	LanM enzymes	dehydration of Ser/Thr before forming thioether link with Cys side chain
Thr	flavin transferase ApbE	transfers a flavin group to the Thr hydroxy group
Trp	flavin-dependent Trp halogen- ases	installs halogen on the C-2
	indole prenyltransferases	transfers prenyl groups to the Trp indole
	hydroxylase BhaQ	converts the benzene ring of Trp to o-hydroxy-p-quinone
	C-mannosyltransferse	catalyzes C-mannosyl glycosylation to the Trp indole ring
Tyr	tyrosinase/catechol O-meth- yltransferase	alkoxylate a Tyr group
	F-prenyltransferases	transfer C5 and C10 prenyl moieties to the O-Tyr
	glycosyltransferase GtfE	transfers sugars to Tyr in vancomycins and teicoplanin-related peptides
Val	N/A	N/A
N-terminus	N-methyltransferases (Mtfadbv and Mtfapek)	catalyze N-terminus methylation of teicoplanin-like heptapeptides
	protease PatA	cleaves peptides following a specific recognition sequence
	ligase subtiligase	ligation between the N at the N-terminus of a peptide and an ester/thioester peptide
	Met and Pro aminopeptidases	excision of Met and Pro in proteins containing Met-Pro-Cys at the N-terminus to expose reactive Cys
C-terminus	tubulin tyrosine ligase	recognizes a tubulin tag sequence at the C-terminus of a protein and installs Tyr-derivatives
N-/C-terminus	dual prenyl and meth- yltransferase AgeMTPT	transfers prenyl and methyl group to the N- and C-terminus of peptides, respectively
	ligase trypsiligase	hydrolyzes peptides with the Tyr-Arg-His tag at the N- or C-terminus between Tyr and Arg and ligates a tag with a guanidinophenyl ester or Arg-His moiety
Cyclization	ligase Omniligase-1	ligation and cyclization of peptides
	cyclodehydratase YcaO (PatG)	N–C macrocyclization
	macrocyclase PsnB	cyclization between Thr and Glu
	macrocyclase PCY1	macrocyclization of peptides with recognition sequence
	cytochrome P450 OxyA-C	catalyze oxidative crosslinking
	subtiligase	macrocyclization of peptides containing 12–31 amino acids