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IUBMB CommentsRequires Mg2+. The enzyme, which participates in the biosynthesis of ribosomal peptide natural products (RiPPs), converts L-cysteine, L-serine and L-threonine residues to thiazoline, oxazoline, and methyloxazoline rings, respectively. The enzyme requires two domains - a cyclodehydratase domain, known as a YcaO domain, and a substrate recognition domain (RRE domain) that controls the regiospecificity of the enzyme. The RRE domain can either be fused to the YcaO domain or occur as a separate protein; however both domains are required for activity. The enzyme can process multiple residues within the same substrate peptide, and all enzymes characterized so far follow a defined order, starting with the L-cysteine closest to the C-terminus. The reaction involves phosphorylation of the preceding ribosomal peptide backbone amide bond, forming ADP and a phosphorylated intermediate, followed by release of the phosphate group. In some cases the enzyme catalyses a side reaction in which the phosphorylated intermediate reacts with ADP to form AMP and diphosphate.
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ATP + a [PatE2]-(L-amino acyl-L-cysteine)
AMP + diphosphate + a [PatE2]-(1S,4R)-2-(C-substituted-aminomethyl)-4-acyl-2-thiazoline
engineered PatE2 protein with single core peptide sequence ITACITFC
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ATP + [BalhA1 variant C40S]-(L-amino acyl-L-serine)
ADP + phosphate + [BalhA1 variant C40S]-(S,S)-2-(Csubstituted-aminomethyl)-4-acyl-2-oxazoline
Bacillus sp. Al Hakam
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ATP + [BalhA1 variant C40T]-(L-amino acyl-L-threonine)
ADP + phosphate + [BalhA1 variant C40T]-(S,S)-2-(C-substituted-aminomethyl)-4-acyl-5-methyl-2-oxazoline
Bacillus sp. Al Hakam
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ATP + [BalhA1]-(L-amino acyl-L-cysteine)
ADP + phosphate + [BalhA1]-(1S,4R)-2-(C-substituted-aminomethyl)-4-acyl-2-thiazoline
Bacillus sp. Al Hakam
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ATP + [PatE2K]-(L-amino acyl-L-cysteine)
ADP + phosphate + [PatE2K]-(1S,4R)-2-(C-substituted-aminomethyl)-4-acyl-2-thiazoline
ATP + [PatE2K]-(L-amino acyl-L-threonine)
ADP + phosphate + [PatE2K]-(S,S)-2-(C-substituted-aminomethyl)-4-acyl-5-methyl-2-oxazoline
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ATP + [PatEalpha]-(L-amino acyl-L-cysteine)
ADP + phosphate + [PatEalpha]-(1S,4R)-2-(C-substituted-aminomethyl)-4-acyl-2-thiazoline
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ATP + [PatEalpha]-(L-amino acyl-L-threonine)
ADP + phosphate + [PatEalpha]-(S,S)-2-(C-substituted-aminomethyl)-4-acyl-5-methyl-2-oxazoline
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ATP + [PatEDm]-(L-amino acyl-L-cysteine)
ADP + phosphate + [PatEDm]-(1S,4R)-2-(C-substituted-aminomethyl)-4-acyl-2-thiazoline
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ATP + [PatEDm]-(L-amino acyl-L-threonine)
ADP + phosphate + [PatEDm]-(S,S)-2-(C-substituted-aminomethyl)-4-acyl-5-methyl-2-oxazoline
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ATP + [TruE2]-(L-amino acyl-L-cysteine)
ADP + phosphate + [TruE2]-(1S,4R)-2-(C-substituted-aminomethyl)-4-acyl-2-thiazoline
ATP + [TruE2]-(L-amino acyl-L-threonine)
ADP + phosphate + [TruE2]-(S,S)-2-(C-substituted-aminomethyl)-4-acyl-5-methyl-2-oxazoline
ATP + [TruE4]-(L-amino acyl-L-cysteine)
ADP + phosphate + [TruE4]-(1S,4R)-2-(C-substituted-aminomethyl)-4-acyl-2-thiazoline
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ATP + [TruE]-(L-amino acyl-L-cysteine)
ADP + phosphate + [TruE]-(1S,4R)-2-(C-substituted-aminomethyl)-4-acyl-2-thiazoline
natural substrate is TruE carrying precursor peptides for patellin 3 and patellin 2
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additional information
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ATP + [PatE2K]-(L-amino acyl-L-cysteine)
ADP + phosphate + [PatE2K]-(1S,4R)-2-(C-substituted-aminomethyl)-4-acyl-2-thiazoline
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ATP + [PatE2K]-(L-amino acyl-L-cysteine)
ADP + phosphate + [PatE2K]-(1S,4R)-2-(C-substituted-aminomethyl)-4-acyl-2-thiazoline
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ATP + [TruE2]-(L-amino acyl-L-cysteine)
ADP + phosphate + [TruE2]-(1S,4R)-2-(C-substituted-aminomethyl)-4-acyl-2-thiazoline
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ATP + [TruE2]-(L-amino acyl-L-cysteine)
ADP + phosphate + [TruE2]-(1S,4R)-2-(C-substituted-aminomethyl)-4-acyl-2-thiazoline
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ATP + [TruE2]-(L-amino acyl-L-cysteine)
ADP + phosphate + [TruE2]-(1S,4R)-2-(C-substituted-aminomethyl)-4-acyl-2-thiazoline
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ATP + [TruE2]-(L-amino acyl-L-cysteine)
ADP + phosphate + [TruE2]-(1S,4R)-2-(C-substituted-aminomethyl)-4-acyl-2-thiazoline
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ATP + [TruE2]-(L-amino acyl-L-threonine)
ADP + phosphate + [TruE2]-(S,S)-2-(C-substituted-aminomethyl)-4-acyl-5-methyl-2-oxazoline
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ATP + [TruE2]-(L-amino acyl-L-threonine)
ADP + phosphate + [TruE2]-(S,S)-2-(C-substituted-aminomethyl)-4-acyl-5-methyl-2-oxazoline
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ATP + [TruE2]-(L-amino acyl-L-threonine)
ADP + phosphate + [TruE2]-(S,S)-2-(C-substituted-aminomethyl)-4-acyl-5-methyl-2-oxazoline
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additional information
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Bacillus sp. Al Hakam
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BalhD thiazole/oxazole synthetase modifies substrate BalhA1 in a unique C- to N-terminal overall direction. The enzyme shows a modest bias for glycine at the preceding (-1) position and a remarkable flexibility in the following (+1) position, even allowing for the incorporation of charged amino acids and bisheterocyclization
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additional information
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in the absence of peptide substrate, MicD is likely catalyzing solely ATP hydrolysis to ADP and then to AMP, while in the presence of substrate, ATP consumption is coupled to heterocyclization. Presence of ATP is required for catalysis. ATP analogue AMP-CPP supports catalysis, while AMP-PCP does not
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additional information
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the order of reaction for threonines is different from that of cysteines and depends in part on a leader peptide within the substrate
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additional information
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in the absence of peptide substrate, MicD is likely catalyzing solely ATP hydrolysis to ADP and then to AMP, while in the presence of substrate, ATP consumption is coupled to heterocyclization. Presence of ATP is required for catalysis. ATP analogue AMP-CPP supports catalysis, while AMP-PCP does not
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additional information
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the order of reaction for threonines is different from that of cysteines and depends in part on a leader peptide within the substrate
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additional information
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presence of ATP is absolutely required. During the course of the reaction, ATP is hydrolyzed to ADP
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additional information
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the precursor peptide leaves the enzyme after the second heterocyclization and before the third heterocyclization
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additional information
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TruD is an adenylase, not a kinase. TruD operates in strict order with the terminal cysteine in the core peptide reacting first, the next most C-terminal cysteine then reacts, and so on
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additional information
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TruD is distributive and stochastic, with no preferred modification order. Under reductive conditions, TruD reacts with the cleaved peptide fragments and heterocyclizes them to completion. Without the addition of reducing agents, the reaction is inhibited. Recognition sequence RSI is not absolutely required for TruD activity, but greatly accelerates the reaction
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physiological function
during biosynthesis, the leader sequence, which PatA cleaves, is required in cis for modification by PatD
physiological function
reaction mechanism, the gamma-phosphate of ATP is transferred in a kinase mechanism to the substrate to yield a phosphorylated intermediate common to all YcaO domain proteins. In cyanobactin heterocyclases, this phosphorylated intermediate, in a proportion of turnovers, reacts with ADP to yield AMP and diphosphate
physiological function
in a kinase mechanism, the gamma-phosphate of ATP is transferred to the substrate to yield a phosphorylated intermediate common to all YcaO domains. In cyanobactin heterocyclases, this phosphorylated intermediate, in a proportion of turnovers, reacts with ADP to yield AMP and diphosphate
physiological function
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reaction mechanism, the gamma-phosphate of ATP is transferred in a kinase mechanism to the substrate to yield a phosphorylated intermediate common to all YcaO domain proteins. In cyanobactin heterocyclases, this phosphorylated intermediate, in a proportion of turnovers, reacts with ADP to yield AMP and diphosphate
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physiological function
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in a kinase mechanism, the gamma-phosphate of ATP is transferred to the substrate to yield a phosphorylated intermediate common to all YcaO domains. In cyanobactin heterocyclases, this phosphorylated intermediate, in a proportion of turnovers, reacts with ADP to yield AMP and diphosphate
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Koehnke, J.; Bent, A.F.; Zollman, D.; Smith, K.; Houssen, W.E.; Zhu, X.; Mann, G.; Lebl, T.; Scharff, R.; Shirran, S.; Botting, C.H.; Jaspars, M.; Schwarz-Linek, U.; Naismith, J.H.
The cyanobactin heterocyclase enzyme a processive adenylase that operates with a defined order of reaction
Angew. Chem. Int. Ed. Engl.
52
13991-13996
2013
uncultured Prochloron sp. 06037A (B2KYG8)
brenda
Ge, Y.; Czekster, C.M.; Miller, O.K.; Botting, C.H.; Schwarz-Linek, U.; Naismith, J.H.
Insights into the mechanism of the cyanobactin heterocyclase enzyme
Biochemistry
58
2125-2132
2019
Microcystis aeruginosa (A8Y998), Microcystis aeruginosa NIES-298 (A8Y998)
brenda
McIntosh, J.A.; Schmidt, E.W.
Marine molecular machines heterocyclization in cyanobactin biosynthesis
ChemBioChem
11
1413-1421
2010
uncultured Prochloron sp. 06037A (B2KYG8), Prochloron didemni (Q52QI6)
brenda
McIntosh, J.A.; Donia, M.S.; Schmidt, E.W.
Insights into heterocyclization from two highly similar enzymes
J. Am. Chem. Soc.
132
4089-4091
2010
Prochloron didemni (Q52QI6)
brenda
Melby, J.O.; Dunbar, K.L.; Trinh, N.Q.; Mitchell, D.A.
Selectivity, directionality, and promiscuity in peptide processing from a Bacillus sp. Al Hakam cyclodehydratase
J. Am. Chem. Soc.
134
5309-5316
2012
Bacillus sp. Al Hakam
brenda
Gu, W.; Sardar, D.; Pierce, E.; Schmidt, E.W.
Roads to Rome role of multiple cassettes in cyanobactin RiPP biosynthesis
J. Am. Chem. Soc.
140
16213-16221
2018
uncultured Prochloron sp. 06037A (B2KYG8)
brenda
6.2.2.2 oxazoline synthase
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