D00267
type: Enzyme
rlcp: p9100
rlcp: p9090
cath: Fumarase C; Chain B, domain 1
cath: Fumarase C; Chain A, domain 2
ec: https://purl.uniprot.org/enzyme/4.3.1.3
csa: 1b8f
uniprot: P21310
kegg enzyme: histidine ammonia-lyase
kegg enzyme: histidase
kegg enzyme: histidinase
kegg enzyme: histidine alpha-deaminase
kegg enzyme: L-histidine ammonia-lyase
kegg pathway: Histidine metabolism
kegg pathway: Nitrogen metabolism
kegg substrate: L-Histidine
kegg substrate: alpha-Amino acid
kegg product: Urocanate
kegg product: 2,3-Ene acid
kegg product: NH3
pdb: 1b8fA01
pdb: 1eb4A01
pdb: 1gk2A01
pdb: 1gk2B01
pdb: 1gk2C01
pdb: 1gk2D01
pdb: 1gk3A01
pdb: 1gkjA01
pdb: 1gkmA01
pdb: 1b8fA02
pdb: 1eb4A02
pdb: 1gk2A02
pdb: 1gk2B02
pdb: 1gk2C02
pdb: 1gk2D02
pdb: 1gk3A02
pdb: 1gkjA02
pdb: 1gkmA02
pdb bound state: Unbound
  compound: L-Histidine
  pdb: 1b8fA01
pdb bound state: Unbound
  compound: L-Histidine
  pdb: 1eb4A01
pdb bound state: Unbound
  compound: L-Histidine
  pdb: 1gk2A01
pdb bound state: Unbound
  compound: L-Histidine
  pdb: 1gk2B01
pdb bound state: Unbound
  compound: L-Histidine
  pdb: 1gk2C01
pdb bound state: Unbound
  compound: L-Histidine
  pdb: 1gk2D01
pdb bound state: Unbound
  compound: L-Histidine
  pdb: 1gk3A01
pdb bound state: Unbound
  compound: L-Histidine
  pdb: 1gkjA01
pdb bound state: Unbound
  compound: L-Histidine
  pdb: 1gkmA01
pdb bound state: Unbound
  compound: L-Histidine
  pdb: 1b8fA02
pdb bound state: Unbound
  compound: L-Histidine
  pdb: 1eb4A02
pdb bound state: Unbound
  compound: L-Histidine
  pdb: 1gk2A02
pdb bound state: Unbound
  compound: L-Histidine
  pdb: 1gk2B02
pdb bound state: Unbound
  compound: L-Histidine
  pdb: 1gk2C02
pdb bound state: Unbound
  compound: L-Histidine
  pdb: 1gk2D02
pdb bound state: Unbound
  compound: L-Histidine
  pdb: 1gk3A02
pdb bound state: Unbound
  compound: L-Histidine
  pdb: 1gkjA02
pdb bound state: Unbound
  compound: L-Histidine
  pdb: 1gkmA02
pdb bound state: Unbound
  compound: alpha-Amino acid
  pdb: 1b8fA01
pdb bound state: Unbound
  compound: alpha-Amino acid
  pdb: 1eb4A01
pdb bound state: Unbound
  compound: alpha-Amino acid
  pdb: 1gk2A01
active site residues resources: An active site homology model of phenylalanine ammonia-lyase from Petroselinum crispum.
active site residues resources: P21310
references: Biostereochemistry of histidine metabolism. II. The steric course of ammonia elimation from L-histidine.
references: Effects of estrogen, glucocorticoid, glucagon, and adenosine 3':5'-monophosphate on catalytic activity, amount, and rate of de novo synthesis of hepatic histidase.
references: Presence and quantity of dehydroalanine in histidine ammonia-lyase from Pseudomonas putida.
references: Identification of Ser143 as the site of modification in the active site of histidine ammonia-lyase.
references: Purification and characterization of Pseudomonas putida histidine ammonia-lyase expressed in Escherichia coli.
references: Ser-143 is an essential active site residue in histidine ammonia-lyase of Pseudomonas putida.
references: Identification of serine-143 as the most likely precursor of dehydroalanine in the active site of histidine ammonia-lyase. A study of the overexpressed enzyme by site-directed mutagenesis.
references: Enzymatic catalysis by Friedel-Crafts-type reactions.
references: Crystallization and preliminary X-ray studies of Pseudomonas putida histidine ammonium-lyase.
references: Crystal structure of histidine ammonia-lyase revealing a novel polypeptide modification as the catalytic electrophile.
references: Homogenization and crystallization of histidine ammonia-lyase by exchange of a surface cysteine residue.
references: Methylidene-imidazolone (MIO) from histidine and phenylalanine ammonia-lyase.
references: Methylidene-imidazolone: a novel electrophile for substrate activation.
references: Characterization of the active site of histidine ammonia-lyase from Pseudomonas putida.
references: Computational analysis of the autocatalytic posttranslational cyclization observed in histidine ammonia-lyase. A comparison with green fluorescent protein.
references: Structures of two histidine ammonia-lyase modifications and implications for the catalytic mechanism.
references: An active site homology model of phenylalanine ammonia-lyase from Petroselinum crispum.
references: Autocatalytic peptide cyclization during chain folding of histidine ammonia-lyase.
comment: According to the literature [10], a prosthetic group, 4-methylidene-imidazole-5-one (MIO), which is formed from Ala-Ser-Gly at positions 142-144, makes an electrophile, which will be a target for a nucleophilic attack. The MIO group can be formed by two water elimination steps. At the first step, the nitrogen atom of Gly144 makes an intramolecular nucleophilic attack at the carbonyl group of Ala142, resulting in a cyclization. At the second step, a water is eliminated from the sidechain of Ser143, forming the MIO group. According to the literature [10], [12], [13] & [16], the reaction proceeds as follows: (A) Addition of imidazole ring to double-bond of MIO group: (A1) The CD atom of the substrate imidazole ring makes a nucleophilic attack on the electrophilic methylidene group of the prosthetic MIO group, forming a covalent (single-bonded) intermediate between the substrate histidine and the MIO group. (A2) The MIO group becomes aromatic with the 143-O anion stabilized by the amide of Gly196, whilst the positive charged imidazole is stabilized by the pi-electrons of Phe329. (B) Isomerization (change in the position of double-bond): (B1) Tyr280' from the adjacent chain acts as a general base, by abstracting H(re) proton from the beta-carbon, which is acidified by the positive charge of the imidazole ring. The oxygen atom of Tyr280' is hydrogen-bonded to Glu414, which seems to modulate the catalytic function of Tyr280'. (C) Elimination of amine group from alpha-carbon is accompanied by elimination of imidazole ring from MIO group: (C1) The rearrangement of the MIO group eliminates the ammonia from the alpha-carbon, generating a double-bond between the beta-carbon and the alpha-carbon. The eliminated ammonia is stabilzed by Tyr53/Asn195/Asn313, whilst 143-O anion is stabilized by the amide of Gly196 (see [16]).

Fumarase C; Chain B, domain 1
type: Cath
references: http://www.cathdb.info/version/latest/superfamily/1.10.275.10
catalytic domain: index.html

Fumarase C; Chain A, domain 2
type: Cath
references: http://www.cathdb.info/version/latest/superfamily/1.20.200.10
catalytic domain: index.html

Histidine metabolism
type: KeggPathway
references: KEGG:MAP00340

Nitrogen metabolism
type: KeggPathway
references: KEGG:MAP00910

L-Histidine
type: KeggSubstrate
references: KEGG:C00135
compound type: amino acids
compound type: aromatic ring (with nitrogen atoms)
references: CHEBI:15971
references: CHEBI:57595
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

alpha-Amino acid
type: KeggSubstrate
references: KEGG:C05167
compound type: amino acids

Urocanate
type: KeggProduct
references: KEGG:C00785
compound type: aromatic ring (with nitrogen atoms)
compound type: carboxyl group
references: CHEBI:30817
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

2,3-Ene acid
type: KeggProduct
references: KEGG:C11823
compound type: carboxyl group

NH3
type: KeggProduct
references: KEGG:C00014
compound type: amine group
compound type: organic ion
references: CHEBI:16134
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

1b8fA01
type: Pdb
references: 1b8f
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1b8f
modified residue: SER 143(dehydroalanine-like)
main chain in catalysis: ALA 142;GLY 144;GLY 196
comment: 142A-143S-144G forming 4-methylidene-imidazole-5-one (MIO)

1eb4A01
type: Pdb
references: 1eb4
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1eb4
modified residue: SER 143(dehydroalanine-like)
main chain in catalysis: ALA 142;GLY 144;GLY 196
comment: 142A-143S-144G forming 4-methylidene-imidazole-5-one (MIO)

1gk2A01
type: Pdb
references: 1gk2
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1gk2
catalytic residue: SER 143
main chain in catalysis: ALA 142;GLY 144;GLY 196

1gk2B01
type: Pdb
references: 1gk2
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1gk2
catalytic residue: SER 143
main chain in catalysis: ALA 142;GLY 144;GLY 196

1gk2C01
type: Pdb
references: 1gk2
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1gk2
catalytic residue: SER 143
main chain in catalysis: ALA 142;GLY 144;GLY 196

1gk2D01
type: Pdb
references: 1gk2
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1gk2
catalytic residue: SER 143
main chain in catalysis: ALA 142;GLY 144;GLY 196

1gk3A01
type: Pdb
references: 1gk3
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1gk3
catalytic residue: SER 143
main chain in catalysis: ALA 142;GLY 144;GLY 196

1gkjA01
type: Pdb
references: 1gkj
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1gkj
modified residue: SER 143(dehydroalanine-like)
main chain in catalysis: ALA 142;GLY 144;GLY 196
comment: 142A-143S-144G forming 4-methylidene-imidazole-5-one (MIO)

1gkmA01
type: Pdb
references: 1gkm
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1gkm
modified residue: SER 143(dehydroalanine-like)
main chain in catalysis: ALA 142;GLY 144;GLY 196
comment: 142A-143S-144G forming 4-methylidene-imidazole-5-one (MIO)

1b8fA02
type: Pdb
references: 1b8f
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1b8f
catalytic residue: TYR 280;PHE 329;GLU 414

1eb4A02
type: Pdb
references: 1eb4
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1eb4
catalytic residue: TYR 280; ;GLU 414
comment: mutant F329A

1gk2A02
type: Pdb
references: 1gk2
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1gk2
catalytic residue: TYR 280; ;GLU 414
comment: mutant F329G

1gk2B02
type: Pdb
references: 1gk2
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1gk2
catalytic residue: TYR 280; ;GLU 414
comment: mutant F329G

1gk2C02
type: Pdb
references: 1gk2
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1gk2
catalytic residue: TYR 280; ;GLU 414
comment: mutant F329G

1gk2D02
type: Pdb
references: 1gk2
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1gk2
catalytic residue: TYR 280; ;GLU 414
comment: mutant F329G

1gk3A02
type: Pdb
references: 1gk3
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1gk3
catalytic residue: TYR 280;PHE 329;GLU 414

1gkjA02
type: Pdb
references: 1gkj
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1gkj
catalytic residue: ;PHE 329;GLU 414
comment: mutant Y280F

1gkmA02
type: Pdb
references: 1gkm
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1gkm
catalytic residue: TYR 280;PHE 329;GLU 414

Biostereochemistry of histidine metabolism. II. The steric course of ammonia elimation from L-histidine.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/4847567
journal: Biochim Biophys Acta
volume: 350
pages: 354-7
published year: 1974
authors:
  item: Sawada S
  item: Tanaka A
  item: Yuzoinouye
  item: Hirasawa T
  item: Soda K

Effects of estrogen, glucocorticoid, glucagon, and adenosine 3':5'-monophosphate on catalytic activity, amount, and rate of de novo synthesis of hepatic histidase.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/193832
journal: J Biol Chem
volume: 252
pages: 3234-9
published year: 1977
authors:
  item: Lamartiniere CA
  item: Feigelson M

Presence and quantity of dehydroalanine in histidine ammonia-lyase from Pseudomonas putida.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/3919759
journal: Biochemistry
volume: 24
pages: 301-8
published year: 1985
authors:
  item: Consevage MW
  item: Phillips AT

Identification of Ser143 as the site of modification in the active site of histidine ammonia-lyase.
type: BibliographicResource
comment: ACTIVE SITE.
medline id: 94058243
references: http://www.ncbi.nlm.nih.gov/pubmed/8239649
journal: Arch Biochem Biophys
volume: 307
pages: 126-32
published year: 1993
authors:
  item: Hernandez D
  item: Stroh JG
  item: Phillips AT
references: P21310

Purification and characterization of Pseudomonas putida histidine ammonia-lyase expressed in Escherichia coli.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/8251759
journal: Protein Expr Purif
volume: 4
pages: 473-8
published year: 1993
authors:
  item: Hernandez D
  item: Phillips AT

Ser-143 is an essential active site residue in histidine ammonia-lyase of Pseudomonas putida.
type: BibliographicResource
comment: ACTIVE SITE, AND MUTAGENESIS.
medline id: 94296420
references: http://www.ncbi.nlm.nih.gov/pubmed/8024588
journal: Biochem Biophys Res Commun
volume: 201
pages: 1433-8
published year: 1994
authors:
  item: Hernandez D
  item: Phillips AT
references: P21310

Identification of serine-143 as the most likely precursor of dehydroalanine in the active site of histidine ammonia-lyase. A study of the overexpressed enzyme by site-directed mutagenesis.
type: BibliographicResource
comment: ACTIVE SITE, AND MUTAGENESIS.
medline id: 94263952
references: http://www.ncbi.nlm.nih.gov/pubmed/8204579
journal: Biochemistry
volume: 33
pages: 6462-7
published year: 1994
authors:
  item: Langer M
  item: Reck G
  item: Reed J
  item: Retey J
references: P21310

Enzymatic catalysis by Friedel-Crafts-type reactions.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/8947915
journal: Naturwissenschaften
volume: 83
pages: 439-47
published year: 1996
authors:
  item: Retey J

Crystallization and preliminary X-ray studies of Pseudomonas putida histidine ammonium-lyase.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/9761874
journal: Acta Crystallogr D Biol Crystallogr
volume: 54
pages: 681-3
published year: 1998
authors:
  item: Teo B
  item: Kidd RD
  item: Mack J
  item: Tiwari A
  item: Hernandez D
  item: Phillips AT
  item: Farber GK

Crystal structure of histidine ammonia-lyase revealing a novel polypeptide modification as the catalytic electrophile.
type: BibliographicResource
comment: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS), AND REVISIONS TO 151 AND 438.
medline id: 99238310
references: http://www.ncbi.nlm.nih.gov/pubmed/10220322
journal: Biochemistry
volume: 38
pages: 5355-61
published year: 1999
authors:
  item: Schwede TF
  item: Retey J
  item: Schulz GE
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: P21310

Homogenization and crystallization of histidine ammonia-lyase by exchange of a surface cysteine residue.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/10195286
journal: Protein Eng
volume: 12
pages: 151-3
published year: 1999
authors:
  item: Schwede TF
  item: Badeker M
  item: Langer M
  item: Retey J
  item: Schulz GE

Methylidene-imidazolone (MIO) from histidine and phenylalanine ammonia-lyase.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/11665488
journal: Adv Protein Chem
volume: 58
pages: 175-214
published year: 2001
authors:
  item: Langer B
  item: Langer M
  item: Retey J

Methylidene-imidazolone: a novel electrophile for substrate activation.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/11578924
journal: Curr Opin Chem Biol
volume: 5
pages: 512-24
published year: 2001
authors:
  item: Poppe L

Characterization of the active site of histidine ammonia-lyase from Pseudomonas putida.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/11732994
journal: Eur J Biochem
volume: 268
pages: 6011-9
published year: 2001
authors:
  item: Rother D
  item: Poppe L
  item: Viergutz S
  item: Langer B
  item: Retey J

Computational analysis of the autocatalytic posttranslational cyclization observed in histidine ammonia-lyase. A comparison with green fluorescent protein.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/11457276
journal: J Am Chem Soc
volume: 123
pages: 4679-86
published year: 2001
authors:
  item: Donnelly M
  item: Fedeles F
  item: Wirstam M
  item: Siegbahn PE
  item: Zimmer M

Structures of two histidine ammonia-lyase modifications and implications for the catalytic mechanism.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/11895450
journal: Eur J Biochem
volume: 269
pages: 1790-7
published year: 2002
authors:
  item: Baedeker M
  item: Schulz GE
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl

An active site homology model of phenylalanine ammonia-lyase from Petroselinum crispum.
type: BibliographicResource
comment: Homologous enzyme
references: http://www.ncbi.nlm.nih.gov/pubmed/12071972
journal: Eur J Biochem
volume: 269
pages: 3065-75
published year: 2002
authors:
  item: Rother D
  item: Poppe L
  item: Morlock G
  item: Viergutz S
  item: Retey J

Autocatalytic peptide cyclization during chain folding of histidine ammonia-lyase.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/11796111
journal: Structure (Camb)
volume: 10
pages: 61-7
published year: 2002
authors:
  item: Baedeker M
  item: Schulz GE
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl

IntermediateAnalogue
pdb: 1gkmA01
ligand het code: CYS-__O-SO4

ReferenceForCatalyticMechanism
reference index: 8
reference section: Fig.6, Fig.7, p.443
reference step: 3

ReferenceForCatalyticMechanism
reference index: 10
reference section: Fig.4, Fig.5, p.5359-5360
reference step: 4

ReferenceForCatalyticMechanism
reference index: 12
reference section: Fig.16, p.190-195
reference step: 4

ReferenceForCatalyticMechanism
reference index: 13
reference section: p.516-518, p.520

ReferenceForCatalyticMechanism
reference index: 14
reference section: Fig.5

ReferenceForCatalyticMechanism
reference index: 15
reference section: Fig.3

ReferenceForCatalyticMechanism
reference index: 16
reference section: Fig.7, p.1794-1796
reference step: 3

ReferenceForCatalyticMechanism
reference index: 18
reference section: Figure 1A, p.62
reference step: 2