ergothioneine biosynthesis I (bacteria)

MetaCyc:PWY-7255

The complete seven-member native pathway combines gamma-glutamylcysteine synthesis, histidine trimethylation, oxygen-dependent C-S coupling, deglutamylation, PLP-dependent cleavage, generic reduction and thiol-thione equilibration. The five named gene products are current Mycolicibacterium smegmatis mc(2)155 proteins; EgtA activity is inferred by similarity, and the early B/C/D reconstitution used DSM43465/ATCC607. Later EgtC and EgtE studies directly identify mc(2)155 constructs. Functional enables assertions retain EgtC tetramer and EgtE homodimer contexts without inventing complex identifiers or monomer sufficiency. Current Rhea defines the first five equations; the terminal native equations retain neutral ergothioneine thiol and thione as separate states. Current Rhea reduction instead uses protonated ergothioneine and an added proton and is not substituted into the neutral tautomer sequence. The AH2/A pair remains generic: DTT-supported experiments do not identify the physiological reductant. Sulfoxide sulfur stereochemistry remains unspecified in the selected authoritative chemical classes, not a claim that every stereoisomer is accepted. Fungal bypasses, disproportionation side products, transport, antioxidant outcomes and precursor biosynthesis are outside this complete native boundary. The 2018 purified EgtD product-inhibition observation (DOI:10.1021/acschembio.8b00127.s001) is retained as DSM43465/ATCC607-derived engineered-preparation context only; it is not transferred to the exact mc(2)155 protein.

Pathway type

ergothioneine biosynthesis

Organism scope

Mycolicibacterium smegmatis MC2 155 NCBITaxon:246196

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Pathway network

37 nodes · 54 asserted directed edges

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Components and activities

Declared biological components and source reaction directions
Node	Kind or role	Source direction
Mycolicibacterium smegmatis MC2 155 `NCBITaxon:246196`	taxon
hydrogen acceptor `CHEBI:13193`	chemical entity
2-sulfenohercynine `CHEBI:136834`	small molecule
pyruvate `CHEBI:15361`	small molecule
water `CHEBI:15377`	small molecule
hydron `CHEBI:15378`	small molecule
dioxygen `CHEBI:15379`	small molecule
N(alpha),N(alpha),N(alpha)-trimethyl-L-histidine `CHEBI:15781`	small molecule
hydrogen donor `CHEBI:17499`	chemical entity
ammonium `CHEBI:28938`	small molecule
iron(2+) `CHEBI:29033`	cofactor
L-glutamate(1-) `CHEBI:29985`	small molecule
ATP(4-) `CHEBI:30616`	small molecule
L-cysteine zwitterion `CHEBI:35235`	small molecule
hydrogenphosphate `CHEBI:43474`	small molecule
ADP(3-) `CHEBI:456216`	small molecule
ergothioneine `CHEBI:4828`	small molecule
L-histidine zwitterion `CHEBI:57595`	small molecule
S-adenosyl-L-homocysteine zwitterion `CHEBI:57856`	small molecule
L-gamma-glutamyl-L-cysteinate(1-) `CHEBI:58173`	small molecule
pyridoxal 5'-phosphate(2-) `CHEBI:597326`	cofactor
S-adenosyl-L-methionine zwitterion `CHEBI:59789`	small molecule
N(alpha)-(L-gamma-glutamyl)-hercynyl-L-cysteine sulfoxide(1-) `CHEBI:82703`	small molecule
hercynylcysteine sulfoxide zwitterion `CHEBI:82706`	small molecule
ergothioneine thione form `CHEBI:82707`	small molecule
Glutamate--cysteine ligase EgtA `UniProtKB:A0R5N1`	protein
Histidine N-alpha-methyltransferase `UniProtKB:A0R5M8`	protein
Hercynine oxygenase `UniProtKB:A0R5N0`	protein
Gamma-glutamyl-hercynylcysteine sulfoxide hydrolase `UniProtKB:A0R5M9`	protein
Hercynylcysteine sulfoxide lyase `UniProtKB:A0R5M7`	protein
L-cysteine + L-glutamate + ATP => gamma-L-glutamyl-L-cysteine + ADP + phosphate + H(+) `RHEA:13286`	molecular activity	left to right
L-histidine + 3 S-adenosyl-L-methionine => hercynine + 3 S-adenosyl-L-homocysteine + 3 H(+) `RHEA:38472`	molecular activity	left to right
gamma-L-glutamyl-L-cysteine + hercynine + O2 => gamma-L-glutamyl-hercynylcysteine S-oxide + H2O `RHEA:42673`	molecular activity	left to right
gamma-L-glutamyl-hercynylcysteine S-oxide + H2O => S-(hercyn-2-yl)-L-cysteine S-oxide + L-glutamate `RHEA:42685`	molecular activity	left to right
S-(hercyn-2-yl)-L-cysteine S-oxide + H2O => 2-sulfenohercynine + pyruvate + NH4(+) `RHEA:52781`	molecular activity	left to right
2-(hydroxysulfanyl)hercynine + a reduced electron acceptor -> ergothioneine + an oxidized electron acceptor + H2O `MetaCyc:RXN-18089`	reaction	left to right
ergothioneine (thione form) ergothioneine `MetaCyc:RXN-15804`	reaction	reversible

Mechanistic edges

Mechanistic edges and their cited evidence
Subject	Predicate and description	Object	Evidence
L-cysteine zwitterion `CHEBI:35235`	consumes	L-cysteine + L-glutamate + ATP => gamma-L-glutamyl-L-cysteine + ADP + phosphate + H(+) `RHEA:13286`	RHEA:13286 Source assertion: RHEA:13286 assigns CHEBI:35235 to its substrates with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/13286']/rh:substrates; rdf:Description[@rdf:about='http://rdf.rhea-db.org/13285_L']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_13285_compound_2467']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_2467)`
L-glutamate(1-) `CHEBI:29985`	consumes	L-cysteine + L-glutamate + ATP => gamma-L-glutamyl-L-cysteine + ADP + phosphate + H(+) `RHEA:13286`	RHEA:13286 Source assertion: RHEA:13286 assigns CHEBI:29985 to its substrates with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/13286']/rh:substrates; rdf:Description[@rdf:about='http://rdf.rhea-db.org/13285_L']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_13285_compound_2079']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_2079)`
ATP(4-) `CHEBI:30616`	consumes	L-cysteine + L-glutamate + ATP => gamma-L-glutamyl-L-cysteine + ADP + phosphate + H(+) `RHEA:13286`	RHEA:13286 Source assertion: RHEA:13286 assigns CHEBI:30616 to its substrates with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/13286']/rh:substrates; rdf:Description[@rdf:about='http://rdf.rhea-db.org/13285_L']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_13285_compound_6372']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_6372)`
L-cysteine + L-glutamate + ATP => gamma-L-glutamyl-L-cysteine + ADP + phosphate + H(+) `RHEA:13286`	produces	L-gamma-glutamyl-L-cysteinate(1-) `CHEBI:58173`	RHEA:13286 Source assertion: RHEA:13286 assigns CHEBI:58173 to its products with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/13286']/rh:products; rdf:Description[@rdf:about='http://rdf.rhea-db.org/13285_R']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_13285_compound_1121']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_1121)`
L-cysteine + L-glutamate + ATP => gamma-L-glutamyl-L-cysteine + ADP + phosphate + H(+) `RHEA:13286`	produces	ADP(3-) `CHEBI:456216`	RHEA:13286 Source assertion: RHEA:13286 assigns CHEBI:456216 to its products with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/13286']/rh:products; rdf:Description[@rdf:about='http://rdf.rhea-db.org/13285_R']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_13285_compound_2710']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_2710)`
L-cysteine + L-glutamate + ATP => gamma-L-glutamyl-L-cysteine + ADP + phosphate + H(+) `RHEA:13286`	produces	hydrogenphosphate `CHEBI:43474`	RHEA:13286 Source assertion: RHEA:13286 assigns CHEBI:43474 to its products with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/13286']/rh:products; rdf:Description[@rdf:about='http://rdf.rhea-db.org/13285_R']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_13285_compound_5518']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_5518)`
L-cysteine + L-glutamate + ATP => gamma-L-glutamyl-L-cysteine + ADP + phosphate + H(+) `RHEA:13286`	produces	hydron `CHEBI:15378`	RHEA:13286 Source assertion: RHEA:13286 assigns CHEBI:15378 to its products with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/13286']/rh:products; rdf:Description[@rdf:about='http://rdf.rhea-db.org/13285_R']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_13285_compound_3249']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_3249)`
L-histidine zwitterion `CHEBI:57595`	consumes	L-histidine + 3 S-adenosyl-L-methionine => hercynine + 3 S-adenosyl-L-homocysteine + 3 H(+) `RHEA:38472`	RHEA:38472 Source assertion: RHEA:38472 assigns CHEBI:57595 to its substrates with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/38472']/rh:substrates; rdf:Description[@rdf:about='http://rdf.rhea-db.org/38471_L']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_38471_compound_3613']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_3613)`
S-adenosyl-L-methionine zwitterion `CHEBI:59789`	consumes Stoichiometric coefficient 3.	L-histidine + 3 S-adenosyl-L-methionine => hercynine + 3 S-adenosyl-L-homocysteine + 3 H(+) `RHEA:38472`	RHEA:38472 Source assertion: RHEA:38472 assigns CHEBI:59789 to its substrates with coefficient 3. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/38472']/rh:substrates; rdf:Description[@rdf:about='http://rdf.rhea-db.org/38471_L']/rh:contains3[@rdf:resource='http://rdf.rhea-db.org/Participant_38471_compound_6127']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_6127)`
L-histidine + 3 S-adenosyl-L-methionine => hercynine + 3 S-adenosyl-L-homocysteine + 3 H(+) `RHEA:38472`	produces	N(alpha),N(alpha),N(alpha)-trimethyl-L-histidine `CHEBI:15781`	RHEA:38472 Source assertion: RHEA:38472 assigns CHEBI:15781 to its products with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/38472']/rh:products; rdf:Description[@rdf:about='http://rdf.rhea-db.org/38471_R']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_38471_compound_4809']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_4809)`
L-histidine + 3 S-adenosyl-L-methionine => hercynine + 3 S-adenosyl-L-homocysteine + 3 H(+) `RHEA:38472`	produces Stoichiometric coefficient 3.	S-adenosyl-L-homocysteine zwitterion `CHEBI:57856`	RHEA:38472 Source assertion: RHEA:38472 assigns CHEBI:57856 to its products with coefficient 3. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/38472']/rh:products; rdf:Description[@rdf:about='http://rdf.rhea-db.org/38471_R']/rh:contains3[@rdf:resource='http://rdf.rhea-db.org/Participant_38471_compound_4281']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_4281)`
L-histidine + 3 S-adenosyl-L-methionine => hercynine + 3 S-adenosyl-L-homocysteine + 3 H(+) `RHEA:38472`	produces Stoichiometric coefficient 3.	hydron `CHEBI:15378`	RHEA:38472 Source assertion: RHEA:38472 assigns CHEBI:15378 to its products with coefficient 3. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/38472']/rh:products; rdf:Description[@rdf:about='http://rdf.rhea-db.org/38471_R']/rh:contains3[@rdf:resource='http://rdf.rhea-db.org/Participant_38471_compound_3249']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_3249)`
L-gamma-glutamyl-L-cysteinate(1-) `CHEBI:58173`	consumes	gamma-L-glutamyl-L-cysteine + hercynine + O2 => gamma-L-glutamyl-hercynylcysteine S-oxide + H2O `RHEA:42673`	RHEA:42673 Source assertion: RHEA:42673 assigns CHEBI:58173 to its substrates with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/42673']/rh:substrates; rdf:Description[@rdf:about='http://rdf.rhea-db.org/42672_L']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_42672_compound_1121']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_1121)`
N(alpha),N(alpha),N(alpha)-trimethyl-L-histidine `CHEBI:15781`	consumes	gamma-L-glutamyl-L-cysteine + hercynine + O2 => gamma-L-glutamyl-hercynylcysteine S-oxide + H2O `RHEA:42673`	RHEA:42673 Source assertion: RHEA:42673 assigns CHEBI:15781 to its substrates with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/42673']/rh:substrates; rdf:Description[@rdf:about='http://rdf.rhea-db.org/42672_L']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_42672_compound_4809']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_4809)`
dioxygen `CHEBI:15379`	consumes	gamma-L-glutamyl-L-cysteine + hercynine + O2 => gamma-L-glutamyl-hercynylcysteine S-oxide + H2O `RHEA:42673`	RHEA:42673 Source assertion: RHEA:42673 assigns CHEBI:15379 to its substrates with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/42673']/rh:substrates; rdf:Description[@rdf:about='http://rdf.rhea-db.org/42672_L']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_42672_compound_1198']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_1198)`
gamma-L-glutamyl-L-cysteine + hercynine + O2 => gamma-L-glutamyl-hercynylcysteine S-oxide + H2O `RHEA:42673`	produces	N(alpha)-(L-gamma-glutamyl)-hercynyl-L-cysteine sulfoxide(1-) `CHEBI:82703`	RHEA:42673 Source assertion: RHEA:42673 assigns CHEBI:82703 to its products with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/42673']/rh:products; rdf:Description[@rdf:about='http://rdf.rhea-db.org/42672_R']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_42672_compound_10177']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_10177)`
gamma-L-glutamyl-L-cysteine + hercynine + O2 => gamma-L-glutamyl-hercynylcysteine S-oxide + H2O `RHEA:42673`	produces	water `CHEBI:15377`	RHEA:42673 Source assertion: RHEA:42673 assigns CHEBI:15377 to its products with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/42673']/rh:products; rdf:Description[@rdf:about='http://rdf.rhea-db.org/42672_R']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_42672_compound_1283']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_1283)`
N(alpha)-(L-gamma-glutamyl)-hercynyl-L-cysteine sulfoxide(1-) `CHEBI:82703`	consumes	gamma-L-glutamyl-hercynylcysteine S-oxide + H2O => S-(hercyn-2-yl)-L-cysteine S-oxide + L-glutamate `RHEA:42685`	RHEA:42685 Source assertion: RHEA:42685 assigns CHEBI:82703 to its substrates with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/42685']/rh:substrates; rdf:Description[@rdf:about='http://rdf.rhea-db.org/42684_L']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_42684_compound_10177']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_10177)`
water `CHEBI:15377`	consumes	gamma-L-glutamyl-hercynylcysteine S-oxide + H2O => S-(hercyn-2-yl)-L-cysteine S-oxide + L-glutamate `RHEA:42685`	RHEA:42685 Source assertion: RHEA:42685 assigns CHEBI:15377 to its substrates with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/42685']/rh:substrates; rdf:Description[@rdf:about='http://rdf.rhea-db.org/42684_L']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_42684_compound_1283']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_1283)`
gamma-L-glutamyl-hercynylcysteine S-oxide + H2O => S-(hercyn-2-yl)-L-cysteine S-oxide + L-glutamate `RHEA:42685`	produces	hercynylcysteine sulfoxide zwitterion `CHEBI:82706`	RHEA:42685 Source assertion: RHEA:42685 assigns CHEBI:82706 to its products with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/42685']/rh:products; rdf:Description[@rdf:about='http://rdf.rhea-db.org/42684_R']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_42684_compound_10178']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_10178)`
gamma-L-glutamyl-hercynylcysteine S-oxide + H2O => S-(hercyn-2-yl)-L-cysteine S-oxide + L-glutamate `RHEA:42685`	produces	L-glutamate(1-) `CHEBI:29985`	RHEA:42685 Source assertion: RHEA:42685 assigns CHEBI:29985 to its products with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/42685']/rh:products; rdf:Description[@rdf:about='http://rdf.rhea-db.org/42684_R']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_42684_compound_2079']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_2079)`
hercynylcysteine sulfoxide zwitterion `CHEBI:82706`	consumes	S-(hercyn-2-yl)-L-cysteine S-oxide + H2O => 2-sulfenohercynine + pyruvate + NH4(+) `RHEA:52781`	RHEA:52781 Source assertion: RHEA:52781 assigns CHEBI:82706 to its substrates with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/52781']/rh:substrates; rdf:Description[@rdf:about='http://rdf.rhea-db.org/52780_L']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_52780_compound_10178']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_10178)`
water `CHEBI:15377`	consumes	S-(hercyn-2-yl)-L-cysteine S-oxide + H2O => 2-sulfenohercynine + pyruvate + NH4(+) `RHEA:52781`	RHEA:52781 Source assertion: RHEA:52781 assigns CHEBI:15377 to its substrates with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/52781']/rh:substrates; rdf:Description[@rdf:about='http://rdf.rhea-db.org/52780_L']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_52780_compound_1283']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_1283)`
S-(hercyn-2-yl)-L-cysteine S-oxide + H2O => 2-sulfenohercynine + pyruvate + NH4(+) `RHEA:52781`	produces	2-sulfenohercynine `CHEBI:136834`	RHEA:52781 Source assertion: RHEA:52781 assigns CHEBI:136834 to its products with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/52781']/rh:products; rdf:Description[@rdf:about='http://rdf.rhea-db.org/52780_R']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_52780_compound_13362']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_13362)`
S-(hercyn-2-yl)-L-cysteine S-oxide + H2O => 2-sulfenohercynine + pyruvate + NH4(+) `RHEA:52781`	produces	pyruvate `CHEBI:15361`	RHEA:52781 Source assertion: RHEA:52781 assigns CHEBI:15361 to its products with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/52781']/rh:products; rdf:Description[@rdf:about='http://rdf.rhea-db.org/52780_R']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_52780_compound_3719']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_3719)`
S-(hercyn-2-yl)-L-cysteine S-oxide + H2O => 2-sulfenohercynine + pyruvate + NH4(+) `RHEA:52781`	produces	ammonium `CHEBI:28938`	RHEA:52781 Source assertion: RHEA:52781 assigns CHEBI:28938 to its products with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/52781']/rh:products; rdf:Description[@rdf:about='http://rdf.rhea-db.org/52780_R']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_52780_compound_1012']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_1012)`
2-sulfenohercynine `CHEBI:136834`	consumes	2-(hydroxysulfanyl)hercynine + a reduced electron acceptor -> ergothioneine + an oxidized electron acceptor + H2O `MetaCyc:RXN-18089`	MetaCyc:RXN-18089 Source assertion: The native left side contains CPD-19388 with implicit coefficient 1. The selected equation retains native neutral ergothioneine and no added proton. Source location `/ptools-xml/Reaction[@frameid='RXN-18089']/left/Compound[@frameid='CPD-19388']; /reaction-direction` MetaCyc:CPD-19388 Source assertion: The sulfenic-acid compound has a CHEBI:136834 unification cross-reference. Source location `/ptools-xml/Compound/dblink[dblink-db='CHEBI']/dblink-oid`
hydrogen donor `CHEBI:17499`	consumes	2-(hydroxysulfanyl)hercynine + a reduced electron acceptor -> ergothioneine + an oxidized electron acceptor + H2O `MetaCyc:RXN-18089`	MetaCyc:RXN-18089 Source assertion: The native left side contains Donor-H2 with implicit coefficient 1. The selected equation retains native neutral ergothioneine and no added proton. Source location `/ptools-xml/Reaction[@frameid='RXN-18089']/left/Compound[@frameid='Donor-H2']; /reaction-direction` MetaCyc:Donor-H2 Source assertion: The native class links CHEBI:17499 and explicitly denotes unknown acceptors transferring two electrons and two protons; its reduced form supplies hydrogen in this reaction. Source location `/ptools-xml/Compound/dblink[dblink-db='CHEBI']; /ptools-xml/Compound/comment, final paragraph`
2-(hydroxysulfanyl)hercynine + a reduced electron acceptor -> ergothioneine + an oxidized electron acceptor + H2O `MetaCyc:RXN-18089`	produces	ergothioneine `CHEBI:4828`	MetaCyc:RXN-18089 Source assertion: The native right side contains Ergothioneine with implicit coefficient 1. The selected equation retains native neutral ergothioneine and no added proton. Source location `/ptools-xml/Reaction[@frameid='RXN-18089']/right/Compound[@frameid='Ergothioneine']; /reaction-direction` MetaCyc:Ergothioneine Source assertion: The native neutral ergothioneine structure has a single C-S bond and a CHEBI:4828 cross-reference. Source location `/ptools-xml/Compound/cml/molecule[@formalCharge='0']/bondArray; /ptools-xml/Compound/dblink[dblink-db='CHEBI']`
2-(hydroxysulfanyl)hercynine + a reduced electron acceptor -> ergothioneine + an oxidized electron acceptor + H2O `MetaCyc:RXN-18089`	produces	hydrogen acceptor `CHEBI:13193`	MetaCyc:RXN-18089 Source assertion: The native right side contains Acceptor with implicit coefficient 1. The selected equation retains native neutral ergothioneine and no added proton. Source location `/ptools-xml/Reaction[@frameid='RXN-18089']/right/Compound[@frameid='Acceptor']; /reaction-direction` MetaCyc:Acceptor Source assertion: The native oxidized acceptor class is explicitly for unknown acceptors transferring two electrons and two protons; its CHEBI:15339 cross-reference is broader than a formula-bearing hydrogen acceptor. Source location `/ptools-xml/Compound/comment, final paragraph; /ptools-xml/Compound/dblink[dblink-db='CHEBI']` CHEBI:13193 Source assertion: CHEBI:13193 is the charge-zero formula-A hydrogen acceptor. It provides the formula-bearing generic oxidized partner, without choosing a physiological donor. Source location `SemanticSQL statements subject CHEBI:13193; rdfs:label, IAO:0000115, chemrof:generalized_empirical_formula, chemrof:charge` RHEA:52785 Source assertion: The independently curated reduction uses CHEBI:17499 as donor and CHEBI:13193 as oxidized partner. Its proton and cationic product convention differs from the selected neutral native equation. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/52785']/rh:substrates and rh:products; participant rh:compound/rh:chebi`
2-(hydroxysulfanyl)hercynine + a reduced electron acceptor -> ergothioneine + an oxidized electron acceptor + H2O `MetaCyc:RXN-18089`	produces	water `CHEBI:15377`	MetaCyc:RXN-18089 Source assertion: The native right side contains WATER with implicit coefficient 1. The selected equation retains native neutral ergothioneine and no added proton. Source location `/ptools-xml/Reaction[@frameid='RXN-18089']/right/Compound[@frameid='WATER']; /reaction-direction`
ergothioneine `CHEBI:4828`	consumes	ergothioneine (thione form) ergothioneine `MetaCyc:RXN-15804`	MetaCyc:RXN-15804 Source assertion: The native right side contains Ergothioneine with implicit coefficient 1. The pathway uses this reversible reaction toward the thione form. Source location `/ptools-xml/Reaction[@frameid='RXN-15804']/right/Compound[@frameid='Ergothioneine']; /reaction-direction` MetaCyc:Ergothioneine Source assertion: The native neutral ergothioneine structure has a single C-S bond and a CHEBI:4828 cross-reference. Source location `/ptools-xml/Compound/cml/molecule[@formalCharge='0']/bondArray; /ptools-xml/Compound/dblink[dblink-db='CHEBI']`
ergothioneine (thione form) ergothioneine `MetaCyc:RXN-15804`	produces	ergothioneine thione form `CHEBI:82707`	MetaCyc:RXN-15804 Source assertion: The native left side contains Ergothioneine-Thione with implicit coefficient 1. The pathway uses this reversible reaction toward the thione form. Source location `/ptools-xml/Reaction[@frameid='RXN-15804']/left/Compound[@frameid='Ergothioneine-Thione']; /reaction-direction` MetaCyc:Ergothioneine-Thione Source assertion: The native neutral thione has a double bond between sulfur atom15 and carbon atom9. A separate thiol frame participates on the other side. Source location `/ptools-xml/Compound/cml/molecule[@formalCharge='0']/bondArray/bond[@atomRefs='Ergothioneine-Thione-atom9 Ergothioneine-Thione-atom15']` CHEBI:82707 Source assertion: CHEBI:82707 specifies neutral ergothioneine thione, formula C9H15N3O2S and a C=S SMILES. Its tautomer-normalized standard InChI alone does not distinguish it from thiol CHEBI:4828. Source location `SemanticSQL statements subject CHEBI:82707; IAO:0000115, chemrof:charge, chemrof:generalized_empirical_formula, chemrof:smiles_string, chemrof:inchi_string`
L-cysteine + L-glutamate + ATP => gamma-L-glutamyl-L-cysteine + ADP + phosphate + H(+) `RHEA:13286`	part_of	`MetaCyc:PWY-7255`	MetaCyc:PWY-7255 Source assertion: The complete pathway reaction-list includes GLUTCYSLIG-RXN. Source location `/ptools-xml/Pathway[@frameid='PWY-7255']/reaction-list/Reaction[@frameid='GLUTCYSLIG-RXN']` MetaCyc:GLUTCYSLIG-RXN Source assertion: The native reaction has Rhea cross-reference 13286. Source location `/ptools-xml/Reaction/dblink[dblink-db='RHEA']/dblink-oid` RHEA:13286 Source assertion: Rhea master 13285 supplies the selected left-to-right reaction RHEA:13286; all chemical sides are taken from that directed record. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/13285']/rh:directionalReaction; rdf:Description[@rdf:about='http://rdf.rhea-db.org/13286']/rh:substrates and rh:products`
L-histidine + 3 S-adenosyl-L-methionine => hercynine + 3 S-adenosyl-L-homocysteine + 3 H(+) `RHEA:38472`	part_of	`MetaCyc:PWY-7255`	MetaCyc:PWY-7255 Source assertion: The complete pathway reaction-list includes RXN-14431. Source location `/ptools-xml/Pathway[@frameid='PWY-7255']/reaction-list/Reaction[@frameid='RXN-14431']` MetaCyc:RXN-14431 Source assertion: The native reaction has Rhea cross-reference 38472. Source location `/ptools-xml/Reaction/dblink[dblink-db='RHEA']/dblink-oid` RHEA:38472 Source assertion: Rhea master 38471 supplies the selected left-to-right reaction RHEA:38472; all chemical sides are taken from that directed record. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/38471']/rh:directionalReaction; rdf:Description[@rdf:about='http://rdf.rhea-db.org/38472']/rh:substrates and rh:products`
gamma-L-glutamyl-L-cysteine + hercynine + O2 => gamma-L-glutamyl-hercynylcysteine S-oxide + H2O `RHEA:42673`	part_of	`MetaCyc:PWY-7255`	MetaCyc:PWY-7255 Source assertion: The complete pathway reaction-list includes RXN-14430. Source location `/ptools-xml/Pathway[@frameid='PWY-7255']/reaction-list/Reaction[@frameid='RXN-14430']` MetaCyc:RXN-14430 Source assertion: The native reaction has Rhea cross-reference 42673. Source location `/ptools-xml/Reaction/dblink[dblink-db='RHEA']/dblink-oid` RHEA:42673 Source assertion: Rhea master 42672 supplies the selected left-to-right reaction RHEA:42673; all chemical sides are taken from that directed record. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/42672']/rh:directionalReaction; rdf:Description[@rdf:about='http://rdf.rhea-db.org/42673']/rh:substrates and rh:products`
gamma-L-glutamyl-hercynylcysteine S-oxide + H2O => S-(hercyn-2-yl)-L-cysteine S-oxide + L-glutamate `RHEA:42685`	part_of	`MetaCyc:PWY-7255`	MetaCyc:PWY-7255 Source assertion: The complete pathway reaction-list includes RXN-14429. Source location `/ptools-xml/Pathway[@frameid='PWY-7255']/reaction-list/Reaction[@frameid='RXN-14429']` MetaCyc:RXN-14429 Source assertion: The native reaction has Rhea cross-reference 42685. Source location `/ptools-xml/Reaction/dblink[dblink-db='RHEA']/dblink-oid` RHEA:42685 Source assertion: Rhea master 42684 supplies the selected left-to-right reaction RHEA:42685; all chemical sides are taken from that directed record. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/42684']/rh:directionalReaction; rdf:Description[@rdf:about='http://rdf.rhea-db.org/42685']/rh:substrates and rh:products`
S-(hercyn-2-yl)-L-cysteine S-oxide + H2O => 2-sulfenohercynine + pyruvate + NH4(+) `RHEA:52781`	part_of	`MetaCyc:PWY-7255`	MetaCyc:PWY-7255 Source assertion: The complete pathway reaction-list includes RXN-18088. Source location `/ptools-xml/Pathway[@frameid='PWY-7255']/reaction-list/Reaction[@frameid='RXN-18088']` MetaCyc:RXN-18088 Source assertion: The native reaction has Rhea cross-reference 52781. Source location `/ptools-xml/Reaction/dblink[dblink-db='RHEA']/dblink-oid` RHEA:52781 Source assertion: Rhea master 52780 supplies the selected left-to-right reaction RHEA:52781; all chemical sides are taken from that directed record. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/52780']/rh:directionalReaction; rdf:Description[@rdf:about='http://rdf.rhea-db.org/52781']/rh:substrates and rh:products`
2-(hydroxysulfanyl)hercynine + a reduced electron acceptor -> ergothioneine + an oxidized electron acceptor + H2O `MetaCyc:RXN-18089`	part_of	`MetaCyc:PWY-7255`	MetaCyc:PWY-7255 Source assertion: The complete pathway reaction-list includes RXN-18089. Source location `/ptools-xml/Pathway[@frameid='PWY-7255']/reaction-list/Reaction[@frameid='RXN-18089']` MetaCyc:RXN-18089 Source assertion: The native reaction is annotated spontaneous; its direction is PHYSIOL-LEFT-TO-RIGHT. Source location `/ptools-xml/Reaction/spontaneous; /ptools-xml/Reaction/reaction-direction` PMID:26149121 Source assertion: With DTT, ergothioneine was the only detected sulfur-containing product of EgtE turnover; without reductant, ergothioneine and sulfinic-acid side product appeared. Potential physiological thiols are suggestions, not identified physiological donors. Source location `/article/body/sec[@id='sec1']/p[3]; /article/body/sec[@id='sec1']/p[5]; Figure 4`
ergothioneine (thione form) ergothioneine `MetaCyc:RXN-15804`	part_of	`MetaCyc:PWY-7255`	MetaCyc:PWY-7255 Source assertion: The complete pathway reaction-list includes RXN-15804. Source location `/ptools-xml/Pathway[@frameid='PWY-7255']/reaction-list/Reaction[@frameid='RXN-15804']` MetaCyc:RXN-15804 Source assertion: The native reaction is annotated spontaneous; its direction is REVERSIBLE. Source location `/ptools-xml/Reaction/spontaneous; /ptools-xml/Reaction/reaction-direction`
Glutamate--cysteine ligase EgtA `UniProtKB:A0R5N1`	enables EgtA glutamate-cysteine ligase activity is annotated by similarity (ECO:0000250 from P9WPK7), not a direct assay of this mc(2)155 protein.	L-cysteine + L-glutamate + ATP => gamma-L-glutamyl-L-cysteine + ADP + phosphate + H(+) `RHEA:13286`	UniProtKB:A0R5N1 Source assertion: The current entry annotates L-cysteine + L-glutamate + ATP = gamma-L-glutamyl-L-cysteine + ADP + phosphate + H(+) with ECO:0000250. Source location `/comments/1/reaction`
Histidine N-alpha-methyltransferase `UniProtKB:A0R5M8`	enables EgtD transfers three SAM methyl groups to histidine; the current entry annotates this activity with ECO:0000269. Primary 2010 and 2014 preparations used DSM43465/ATCC607, not mc(2)155. The earlier engineered preparation differs at residue 2 from the current sequence (A versus T). No functional consequence of this residue difference is inferred.	L-histidine + 3 S-adenosyl-L-methionine => hercynine + 3 S-adenosyl-L-homocysteine + 3 H(+) `RHEA:38472`	UniProtKB:A0R5M8 Source assertion: The current entry annotates L-histidine + 3 S-adenosyl-L-methionine = hercynine + 3 S-adenosyl-L-homocysteine + 3 H(+) with ECO:0000269. Its complete current sequence begins MTLSLANY. Source location `/comments/1/reaction; /sequence/value` DOI:10.1021/ja101721e.s001 Source assertion: The cloned egtB/C/D genes were amplified from M. smegmatis DSM43465 and expressed in E. coli BL21; the selected sections report the relevant reconstituted activity. Source location `S2-S4, Cloning pS2; Production of EgtB, EgtC and EgtD; EgtD activity` PMID:24817736 Source assertion: The DSM43465/ATCC607 EgtD construct eluted as a monomer by preparative and analytical size-exclusion chromatography; crystal asymmetric-unit multiplicity is not the solution oligomer. The Methods give the tagged construct sequence with a MALSLANY protein start. Source location `HTML section id='sec2.1', paragraphs 1-2; section id='sec3', paragraph 1`
Hercynine oxygenase `UniProtKB:A0R5N0`	enables EgtB oxidative C-S coupling is annotated with ECO:0000269. The 2010 enzyme preparation used DSM43465; the 2015 structural co-citation studies M. thermoresistibile. Neither establishes a mc(2)155 solution assembly.	gamma-L-glutamyl-L-cysteine + hercynine + O2 => gamma-L-glutamyl-hercynylcysteine S-oxide + H2O `RHEA:42673`	UniProtKB:A0R5N0 Source assertion: The current entry annotates gamma-L-glutamyl-L-cysteine + hercynine + O2 = gamma-L-glutamyl-hercynylcysteine S-oxide + H2O with ECO:0000269. Source location `/comments/1/reaction` DOI:10.1021/ja101721e.s001 Source assertion: The cloned egtB/C/D genes were amplified from M. smegmatis DSM43465 and expressed in E. coli BL21; the selected sections report the relevant reconstituted activity. Source location `S2-S3 and S5-S9, Cloning pS2; EgtB reaction/product and metal/substrate tests`
Gamma-glutamyl-hercynylcysteine sulfoxide hydrolase `UniProtKB:A0R5M9`	enables EgtC hydrolyses the gamma-glutamyl moiety (ECO:0000269). Functional enables retains its experimentally supported tetramer assembly context; it does not assert isolated-monomer sufficiency.	gamma-L-glutamyl-hercynylcysteine S-oxide + H2O => S-(hercyn-2-yl)-L-cysteine S-oxide + L-glutamate `RHEA:42685`	UniProtKB:A0R5M9 Source assertion: The current entry annotates gamma-L-glutamyl-hercynylcysteine S-oxide + H2O = S-(hercyn-2-yl)-L-cysteine S-oxide + L-glutamate with ECO:0000269. Source location `/comments/1/reaction` DOI:10.1021/ja101721e.s001 Source assertion: The cloned egtB/C/D genes were amplified from M. smegmatis DSM43465 and expressed in E. coli BL21; the selected sections report the relevant reconstituted activity. Source location `S2-S3 and S10, Cloning pS2; combined enzymatic ergothioneine synthesis` PMID:26079795 Source assertion: The authors cloned A0R5M9/MSMEG_6248 from mc(2)155/ATCC700084 and report a tetramer supported by PISA and analytical size-exclusion chromatography. Their substrate-bound structure used a C2A variant. Source location `Accepted manuscript PDF p2, Results and Discussion / Overall structure; pp5-6, Experimental Section / Protein production`
Hercynylcysteine sulfoxide lyase `UniProtKB:A0R5M7`	enables EgtE cleavage produces sulfenohercynine, pyruvate and ammonium (ECO:0000269). Functional enables retains the solution-supported homodimer; subsequent reduction is not assigned as a separate EgtE catalytic reaction.	S-(hercyn-2-yl)-L-cysteine S-oxide + H2O => 2-sulfenohercynine + pyruvate + NH4(+) `RHEA:52781`	UniProtKB:A0R5M7 Source assertion: The current entry annotates S-(hercyn-2-yl)-L-cysteine S-oxide + H2O = 2-sulfenohercynine + pyruvate + NH4(+) with ECO:0000269. Source location `/comments/2/reaction` PMID:26149121 Source assertion: The purified PLP enzyme converted the sulfoxide to a trapped sulfenic-acid intermediate; DTT yielded ergothioneine with pyruvate and ammonia. The particular physiological reductant was not established. Source location `/article/body/sec[@id='sec1']/p[position()>=3 and position()<=8]; Figures 4-6` PMID:38072054 Source assertion: The full A0R5M7/MSMEG_6246 coding region came from mc2155. Crystal and solution chromatography support a homodimer; the substrate pocket includes residues from the neighboring monomer. Source location `/article/body/sec[@id='sec3']/sec[@id='sec3.2']/p[1]; /article/body/sec[@id='sec1']/sec[@id='sec1.1']/p[2]; sec[@id='sec1.2']/p[1]`
Hercynine oxygenase `UniProtKB:A0R5N0`	has_cofactor	iron(2+) `CHEBI:29033`	UniProtKB:A0R5N0 Source assertion: Fe(2+) is annotated as EgtB cofactor with ECO:0000269 evidence. Source location `/comments/2/cofactors/0` DOI:10.1021/ja101721e.s001 Source assertion: Chelex treatment reduced activity of the DSM43465 EgtB preparation; FeSO4 restored sulfoxide formation, unlike the tested Zn, Cu or Mn conditions. Source location `S7, Figure S6 and paragraph describing metal depletion/reconstitution`
Hercynylcysteine sulfoxide lyase `UniProtKB:A0R5M7`	has_cofactor	pyridoxal 5'-phosphate(2-) `CHEBI:597326`	UniProtKB:A0R5M7 Source assertion: Pyridoxal 5'-phosphate is annotated as EgtE cofactor with ECO:0000269. Source location `/comments/3/cofactors/0` PMID:26149121 Source assertion: Purified EgtE displayed a PLP-associated 420 nm absorbance and contained approximately 0.8 mol PLP per mol enzyme monomer. Source location `/article/body/sec[@id='sec1']/p[1]`
Histidine N-alpha-methyltransferase `UniProtKB:A0R5M8`	enables	`MetaCyc:PWY-7255`	PMID:23629716 Source assertion: M. smegmatis mc2155 lacking egtD lost detectable ergothioneine synthesis; complementation restored production. This establishes pathway physiology, not direct validation of all seven individual reaction states. Source location `HTML section id='sec5', paragraph 1; section id='sec12', paragraph 1; Table 3`
L-cysteine + L-glutamate + ATP => gamma-L-glutamyl-L-cysteine + ADP + phosphate + H(+) `RHEA:13286`	provides_input_for Shared chemical: CHEBI:58173.	gamma-L-glutamyl-L-cysteine + hercynine + O2 => gamma-L-glutamyl-hercynylcysteine S-oxide + H2O `RHEA:42673`	MetaCyc:PWY-7255 Source assertion: Native reaction ordering and layout connect GLUTCYSLIG-RXN to RXN-14430. Source location `/ptools-xml/Pathway/reaction-ordering; /ptools-xml/Pathway/reaction-layout[Reaction/@frameid='GLUTCYSLIG-RXN' or Reaction/@frameid='RXN-14430']` RHEA:13286 Source assertion: RHEA:13286 assigns CHEBI:58173 to its products with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/13286']/rh:products; rdf:Description[@rdf:about='http://rdf.rhea-db.org/13285_R']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_13285_compound_1121']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_1121)` RHEA:42673 Source assertion: RHEA:42673 assigns CHEBI:58173 to its substrates with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/42673']/rh:substrates; rdf:Description[@rdf:about='http://rdf.rhea-db.org/42672_L']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_42672_compound_1121']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_1121)`
L-histidine + 3 S-adenosyl-L-methionine => hercynine + 3 S-adenosyl-L-homocysteine + 3 H(+) `RHEA:38472`	provides_input_for Shared chemical: CHEBI:15781.	gamma-L-glutamyl-L-cysteine + hercynine + O2 => gamma-L-glutamyl-hercynylcysteine S-oxide + H2O `RHEA:42673`	MetaCyc:PWY-7255 Source assertion: Native reaction ordering and layout connect RXN-14431 to RXN-14430. Source location `/ptools-xml/Pathway/reaction-ordering; /ptools-xml/Pathway/reaction-layout[Reaction/@frameid='RXN-14431' or Reaction/@frameid='RXN-14430']` RHEA:38472 Source assertion: RHEA:38472 assigns CHEBI:15781 to its products with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/38472']/rh:products; rdf:Description[@rdf:about='http://rdf.rhea-db.org/38471_R']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_38471_compound_4809']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_4809)` RHEA:42673 Source assertion: RHEA:42673 assigns CHEBI:15781 to its substrates with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/42673']/rh:substrates; rdf:Description[@rdf:about='http://rdf.rhea-db.org/42672_L']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_42672_compound_4809']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_4809)`
gamma-L-glutamyl-L-cysteine + hercynine + O2 => gamma-L-glutamyl-hercynylcysteine S-oxide + H2O `RHEA:42673`	provides_input_for Shared chemical: CHEBI:82703.	gamma-L-glutamyl-hercynylcysteine S-oxide + H2O => S-(hercyn-2-yl)-L-cysteine S-oxide + L-glutamate `RHEA:42685`	MetaCyc:PWY-7255 Source assertion: Native reaction ordering and layout connect RXN-14430 to RXN-14429. Source location `/ptools-xml/Pathway/reaction-ordering; /ptools-xml/Pathway/reaction-layout[Reaction/@frameid='RXN-14430' or Reaction/@frameid='RXN-14429']` RHEA:42673 Source assertion: RHEA:42673 assigns CHEBI:82703 to its products with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/42673']/rh:products; rdf:Description[@rdf:about='http://rdf.rhea-db.org/42672_R']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_42672_compound_10177']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_10177)` RHEA:42685 Source assertion: RHEA:42685 assigns CHEBI:82703 to its substrates with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/42685']/rh:substrates; rdf:Description[@rdf:about='http://rdf.rhea-db.org/42684_L']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_42684_compound_10177']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_10177)`
gamma-L-glutamyl-hercynylcysteine S-oxide + H2O => S-(hercyn-2-yl)-L-cysteine S-oxide + L-glutamate `RHEA:42685`	provides_input_for Shared chemical: CHEBI:82706.	S-(hercyn-2-yl)-L-cysteine S-oxide + H2O => 2-sulfenohercynine + pyruvate + NH4(+) `RHEA:52781`	MetaCyc:PWY-7255 Source assertion: Native reaction ordering and layout connect RXN-14429 to RXN-18088. Source location `/ptools-xml/Pathway/reaction-ordering; /ptools-xml/Pathway/reaction-layout[Reaction/@frameid='RXN-14429' or Reaction/@frameid='RXN-18088']` RHEA:42685 Source assertion: RHEA:42685 assigns CHEBI:82706 to its products with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/42685']/rh:products; rdf:Description[@rdf:about='http://rdf.rhea-db.org/42684_R']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_42684_compound_10178']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_10178)` RHEA:52781 Source assertion: RHEA:52781 assigns CHEBI:82706 to its substrates with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/52781']/rh:substrates; rdf:Description[@rdf:about='http://rdf.rhea-db.org/52780_L']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_52780_compound_10178']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_10178)`
S-(hercyn-2-yl)-L-cysteine S-oxide + H2O => 2-sulfenohercynine + pyruvate + NH4(+) `RHEA:52781`	provides_input_for Shared chemical: CHEBI:136834.	2-(hydroxysulfanyl)hercynine + a reduced electron acceptor -> ergothioneine + an oxidized electron acceptor + H2O `MetaCyc:RXN-18089`	MetaCyc:PWY-7255 Source assertion: Native reaction ordering and layout connect RXN-18088 to RXN-18089. Source location `/ptools-xml/Pathway/reaction-ordering; /ptools-xml/Pathway/reaction-layout[Reaction/@frameid='RXN-18088' or Reaction/@frameid='RXN-18089']` RHEA:52781 Source assertion: RHEA:52781 assigns CHEBI:136834 to its products with coefficient 1. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/52781']/rh:products; rdf:Description[@rdf:about='http://rdf.rhea-db.org/52780_R']/rh:contains1[@rdf:resource='http://rdf.rhea-db.org/Participant_52780_compound_13362']; rh:compound/rh:chebi (http://rdf.rhea-db.org/Compound_13362)` MetaCyc:RXN-18089 Source assertion: The native left side contains CPD-19388 with implicit coefficient 1. The selected equation retains native neutral ergothioneine and no added proton. Source location `/ptools-xml/Reaction[@frameid='RXN-18089']/left/Compound[@frameid='CPD-19388']; /reaction-direction` MetaCyc:CPD-19388 Source assertion: The sulfenic-acid compound has a CHEBI:136834 unification cross-reference. Source location `/ptools-xml/Compound/dblink[dblink-db='CHEBI']/dblink-oid`
2-(hydroxysulfanyl)hercynine + a reduced electron acceptor -> ergothioneine + an oxidized electron acceptor + H2O `MetaCyc:RXN-18089`	provides_input_for Shared chemical: CHEBI:4828.	ergothioneine (thione form) ergothioneine `MetaCyc:RXN-15804`	MetaCyc:PWY-7255 Source assertion: Native reaction ordering and layout connect RXN-18089 to RXN-15804. Source location `/ptools-xml/Pathway/reaction-ordering; /ptools-xml/Pathway/reaction-layout[Reaction/@frameid='RXN-18089' or Reaction/@frameid='RXN-15804']` MetaCyc:RXN-18089 Source assertion: The native right side contains Ergothioneine with implicit coefficient 1. The selected equation retains native neutral ergothioneine and no added proton. Source location `/ptools-xml/Reaction[@frameid='RXN-18089']/right/Compound[@frameid='Ergothioneine']; /reaction-direction` MetaCyc:Ergothioneine Source assertion: The native neutral ergothioneine structure has a single C-S bond and a CHEBI:4828 cross-reference. Source location `/ptools-xml/Compound/cml/molecule[@formalCharge='0']/bondArray; /ptools-xml/Compound/dblink[dblink-db='CHEBI']` MetaCyc:RXN-15804 Source assertion: The native right side contains Ergothioneine with implicit coefficient 1. The pathway uses this reversible reaction toward the thione form. Source location `/ptools-xml/Reaction[@frameid='RXN-15804']/right/Compound[@frameid='Ergothioneine']; /reaction-direction` MetaCyc:Ergothioneine Source assertion: The native neutral ergothioneine structure has a single C-S bond and a CHEBI:4828 cross-reference. Source location `/ptools-xml/Compound/cml/molecule[@formalCharge='0']/bondArray; /ptools-xml/Compound/dblink[dblink-db='CHEBI']`

References

MetaCyc:PWY-7255 ergothioneine biosynthesis I (bacteria) (source version: MetaCyc 22.5 public mirror; complete original XML response retrieved 2026-10-11)
MetaCyc:GLUTCYSLIG-RXN GLUTCYSLIG-RXN (source version: MetaCyc 22.5 public mirror; complete original XML response retrieved 2026-10-11)
MetaCyc:RXN-14431 RXN-14431 (source version: MetaCyc 22.5 public mirror; complete original XML response retrieved 2026-10-11)
MetaCyc:RXN-14430 RXN-14430 (source version: MetaCyc 22.5 public mirror; complete original XML response retrieved 2026-10-11)
MetaCyc:RXN-14429 RXN-14429 (source version: MetaCyc 22.5 public mirror; complete original XML response retrieved 2026-10-11)
MetaCyc:RXN-18088 RXN-18088 (source version: MetaCyc 22.5 public mirror; complete original XML response retrieved 2026-10-11)
MetaCyc:RXN-18089 RXN-18089 (source version: MetaCyc 22.5 public mirror; complete original XML response retrieved 2026-10-11)
MetaCyc:RXN-15804 RXN-15804 (source version: MetaCyc 22.5 public mirror; complete original XML response retrieved 2026-10-11)
MetaCyc:CPD-19388 2-(hydroxysulfanyl)hercynine (source version: MetaCyc 22.5 public mirror; complete original XML response retrieved 2026-10-11)
MetaCyc:Ergothioneine ergothioneine (source version: MetaCyc 22.5 public mirror; complete original XML response retrieved 2026-10-11)
MetaCyc:Ergothioneine-Thione ergothioneine (thione form) (source version: MetaCyc 22.5 public mirror; complete original XML response retrieved 2026-10-11)
MetaCyc:Donor-H2 a reduced electron acceptor (source version: MetaCyc 22.5 public mirror; complete original XML response retrieved 2026-10-11)
MetaCyc:Acceptor an oxidized electron acceptor (source version: MetaCyc 22.5 public mirror; complete original XML response retrieved 2026-10-11)
UniProtKB:A0R5N1 Glutamate--cysteine ligase EgtA (source version: Complete current original JSON retrieved 2026-10-11; entry version 108, annotation date 2026-06-10; release headers not retained)
UniProtKB:A0R5M8 Histidine N-alpha-methyltransferase (source version: Complete current original JSON retrieved 2026-10-11; entry version 114, annotation date 2026-09-02; release headers not retained)
UniProtKB:A0R5N0 Hercynine oxygenase (source version: Complete current original JSON retrieved 2026-10-11; entry version 112, annotation date 2026-09-02; release headers not retained)
UniProtKB:A0R5M9 Gamma-glutamyl-hercynylcysteine sulfoxide hydrolase (source version: Complete current original JSON retrieved 2026-10-11; entry version 103, annotation date 2026-06-10; release headers not retained)
UniProtKB:A0R5M7 Hercynylcysteine sulfoxide lyase (source version: Complete current original JSON retrieved 2026-10-11; entry version 111, annotation date 2026-09-02; release headers not retained)
RHEA:13286 Rhea 142 directed reaction 13286 and family (source version: Rhea 142, 2026-09-02; SHA256 covers complete official compressed RDF gzip)
RHEA:38472 Rhea 142 directed reaction 38472 and family (source version: Rhea 142, 2026-09-02; SHA256 covers complete official compressed RDF gzip)
RHEA:42673 Rhea 142 directed reaction 42673 and family (source version: Rhea 142, 2026-09-02; SHA256 covers complete official compressed RDF gzip)
RHEA:42685 Rhea 142 directed reaction 42685 and family (source version: Rhea 142, 2026-09-02; SHA256 covers complete official compressed RDF gzip)
RHEA:52781 Rhea 142 directed reaction 52781 and family (source version: Rhea 142, 2026-09-02; SHA256 covers complete official compressed RDF gzip)
RHEA:52785 Rhea 142 directed reaction 52785 and family (source version: Rhea 142, 2026-09-02; SHA256 covers complete official compressed RDF gzip)
CHEBI:4828 ergothioneine (source version: ChEBI 255; source_sha256 covers complete pinned original SemanticSQL database, not the linked HTML page; subject-specific fields inspected)
CHEBI:82707 ergothioneine thione form (source version: ChEBI 255; source_sha256 covers complete pinned original SemanticSQL database, not the linked HTML page; subject-specific fields inspected)
CHEBI:13193 hydrogen acceptor (source version: ChEBI 255; source_sha256 covers complete pinned original SemanticSQL database, not the linked HTML page; subject-specific fields inspected)
CHEBI:17499 hydrogen donor (source version: ChEBI 255; source_sha256 covers complete pinned original SemanticSQL database, not the linked HTML page; subject-specific fields inspected)
DOI:10.1021/ja101721e.s001 In vitro reconstitution of mycobacterial ergothioneine biosynthesis: Supporting Information (source version: Original 17-page ACS supplementary PDF; DOI association verified in original Figshare article 2768629)
PMID:26149121 Mechanistic studies of a novel C-S lyase in ergothioneine biosynthesis: the involvement of a sulfenic acid intermediate (source version: Complete original 2015 JATS XML; byte-identical copy of source acquired 2026-10-11T07:45:43.069019+00:00)
PMID:38072054 Structure of mycobacterial ergothioneine-biosynthesis C-S lyase EgtE (source version: Complete original JATS XML; article published 2023, collection 2024; retrieved 2026-10-11)
PMID:26079795 Structure of the ergothioneine-biosynthetic amidohydrolase EgtC (source version: Complete 9-page accepted author manuscript; manuscript PDF, not typeset version of record; retrieved 2026-10-11)
PMID:24817736 Crystallization and preliminary X-ray analysis of the ergothioneine-biosynthetic methyltransferase EgtD (source version: Complete original 2014 PMC HTML response; retrieved 2026-10-11)
PMID:23629716 Ergothioneine is a secreted antioxidant in Mycobacterium smegmatis (source version: Complete original 2013 PMC HTML response; retrieved 2026-10-11)
DOI:10.1021/acschembio.8b00127.s001 Inhibition and regulation of the ergothioneine biosynthetic methyltransferase EgtD: Supporting information (source version: Complete original 25-page ACS supplementary PDF; DOI association verified in Figshare article 6144188; retrieved 2026-10-11)

Curation history

2026-10-11T09:04:16Z codex
- CREATE — Add ergothioneine biosynthesis I (bacteria)
  Curated all seven native bacterial ergothioneine reactions with strain-qualified protein evidence, separate thiol/thione forms and an explicitly unresolved physiological reductant. Maintained record MetaCyc:PWY-7255; creation bytes SHA256 a0a26b897757e072ec5640805db8ab9ed0961b6499e1c576d0751996a0f97b37. Original-source projections, replay and identifier decisions are in research/pathway_additions/2026-10-11-next-203/. Duplicate searches included ignored and hidden files. Independent review and full integration gates are separate subsequent checks, not claimed by this creation event.
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2026-10-11T09:19:47Z codex
- EDIT — Qualify EgtD product inhibition to the assayed preparation
  Removed the hercynine inhibits exact mc(2)155 A0R5M8 edge because the cited engineered EgtD preparation derives from ATCC607/DSM43465 and differs at residue 2 from the current entry. Retained the observed in vitro inhibition as explicitly scoped preparation context; this does not refute its biology. Tightened the existing activity evidence construct/sequence locator without transferring inhibition-only evidence to that edge. All seven native transformations, 33 chemical sides, participants and references are preserved. Initial independent finding and all reviewed inputs remain immutable; the successor review and final integration gates are separate checks. Corrected maintained SHA256 238df68728e041e3afe989e226cecf689924db2318fc51dd700b9028f6920527.
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