DB code: D00267

RLCP classification 5.104.2187000.9100 : Elimination
5.204.2187010.9090 : Elimination
CATH domain 1.10.275.10 : Fumarase C; Chain B, domain 1 Catalytic domain
1.20.200.10 : Fumarase C; Chain A, domain 2 Catalytic domain
E.C. 4.3.1.3
CSA 1b8f
M-CSA 1b8f
MACiE

CATH domain Related DB codes (homologues)
1.10.275.10 : Fumarase C; Chain B, domain 1 T00086 T00092 T00094 T00095
1.20.200.10 : Fumarase C; Chain A, domain 2 T00086 T00092 T00094 T00095

Uniprot Enzyme Name
UniprotKB Protein name Synonyms Pfam
P21310 Histidine ammonia-lyase
Histidase
EC 4.3.1.3
PF00221 (Lyase_aromatic)
[Graphical View]

KEGG enzyme name
histidine ammonia-lyase
histidase
histidinase
histidine alpha-deaminase
L-histidine ammonia-lyase

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P21310 HUTH_PSEPU L-histidine = urocanate + NH(3). Homotetramer. Cytoplasm (Potential).

KEGG Pathways
Map code Pathways E.C.
MAP00340 Histidine metabolism
MAP00910 Nitrogen metabolism

Compound table
Substrates Products Intermediates
KEGG-id C00135 C05167 C00785 C11823 C00014
E.C.
Compound L-Histidine alpha-Amino acid Urocanate 2,3-Ene acid NH3
Type amino acids,aromatic ring (with nitrogen atoms) amino acids aromatic ring (with nitrogen atoms),carboxyl group carboxyl group amine group,organic ion
ChEBI 15971
 57595
 15971
 57595
 		30817
 30817
 		16134
 16134
PubChem 6274
 6971009
 6274
 6971009
 		736715
 736715
 		222
 222
1b8fA01 Unbound Unbound Unbound Unbound Unbound Unbound
1eb4A01 Unbound Unbound Unbound Unbound Unbound Unbound
1gk2A01 Unbound Unbound Unbound Unbound Unbound Unbound
1gk2B01 Unbound Unbound Unbound Unbound Unbound Unbound
1gk2C01 Unbound Unbound Unbound Unbound Unbound Unbound
1gk2D01 Unbound Unbound Unbound Unbound Unbound Unbound
1gk3A01 Unbound Unbound Unbound Unbound Unbound Unbound
1gkjA01 Unbound Unbound Unbound Unbound Unbound Unbound
1gkmA01 Unbound Unbound Unbound Unbound Unbound Intermediate-analogue:CYS-__O-SO4
1b8fA02 Unbound Unbound Unbound Unbound Unbound Unbound
1eb4A02 Unbound Unbound Unbound Unbound Unbound Unbound
1gk2A02 Unbound Unbound Unbound Unbound Unbound Unbound
1gk2B02 Unbound Unbound Unbound Unbound Unbound Unbound
1gk2C02 Unbound Unbound Unbound Unbound Unbound Unbound
1gk2D02 Unbound Unbound Unbound Unbound Unbound Unbound
1gk3A02 Unbound Unbound Unbound Unbound Unbound Unbound
1gkjA02 Unbound Unbound Unbound Unbound Unbound Unbound
1gkmA02 Unbound Unbound Unbound Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.
Swiss-prot;P21310 & literature [16]

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1b8fA01 SER 143(dehydroalanine-like) ALA 142;GLY 144;GLY 196 142A-143S-144G forming 4-methylidene-imidazole-5-one (MIO)
1eb4A01 SER 143(dehydroalanine-like) ALA 142;GLY 144;GLY 196 142A-143S-144G forming 4-methylidene-imidazole-5-one (MIO)
1gk2A01 SER 143 ALA 142;GLY 144;GLY 196
1gk2B01 SER 143 ALA 142;GLY 144;GLY 196
1gk2C01 SER 143 ALA 142;GLY 144;GLY 196
1gk2D01 SER 143 ALA 142;GLY 144;GLY 196
1gk3A01 SER 143 ALA 142;GLY 144;GLY 196
1gkjA01 SER 143(dehydroalanine-like) ALA 142;GLY 144;GLY 196 142A-143S-144G forming 4-methylidene-imidazole-5-one (MIO)
1gkmA01 SER 143(dehydroalanine-like) ALA 142;GLY 144;GLY 196 142A-143S-144G forming 4-methylidene-imidazole-5-one (MIO)
1b8fA02 TYR 280;PHE 329;GLU 414
1eb4A02 TYR 280;;GLU 414 mutant F329A
1gk2A02 TYR 280;;GLU 414 mutant F329G
1gk2B02 TYR 280;;GLU 414 mutant F329G
1gk2C02 TYR 280;;GLU 414 mutant F329G
1gk2D02 TYR 280;;GLU 414 mutant F329G
1gk3A02 TYR 280;PHE 329;GLU 414
1gkjA02 ;PHE 329;GLU 414 mutant Y280F
1gkmA02 TYR 280;PHE 329;GLU 414

References for Catalytic Mechanism
References Sections No. of steps in catalysis
[8]
Fig.6, Fig.7, p.443 3
[10]
Fig.4, Fig.5, p.5359-5360 4
[12]
Fig.16, p.190-195 4
[13]
p.516-518, p.520
[14]
Fig.5
[15]
Fig.3
[16]
Fig.7, p.1794-1796 3
[18]
Figure 1A, p.62 2

References
[1]
Resource
Comments
Medline ID
PubMed ID 4847567
Journal Biochim Biophys Acta
Year 1974
Volume 350
Pages 354-7
Authors Sawada S, Tanaka A, Yuzoinouye, Hirasawa T, Soda K
Title Biostereochemistry of histidine metabolism. II. The steric course of ammonia elimation from L-histidine.
Related PDB
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID 193832
Journal J Biol Chem
Year 1977
Volume 252
Pages 3234-9
Authors Lamartiniere CA, Feigelson M
Title Effects of estrogen, glucocorticoid, glucagon, and adenosine 3':5'-monophosphate on catalytic activity, amount, and rate of de novo synthesis of hepatic histidase.
Related PDB
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID 3919759
Journal Biochemistry
Year 1985
Volume 24
Pages 301-8
Authors Consevage MW, Phillips AT
Title Presence and quantity of dehydroalanine in histidine ammonia-lyase from Pseudomonas putida.
Related PDB
Related UniProtKB
[4]
Resource
Comments ACTIVE SITE.
Medline ID 94058243
PubMed ID 8239649
Journal Arch Biochem Biophys
Year 1993
Volume 307
Pages 126-32
Authors Hernandez D, Stroh JG, Phillips AT
Title Identification of Ser143 as the site of modification in the active site of histidine ammonia-lyase.
Related PDB
Related UniProtKB P21310
[5]
Resource
Comments
Medline ID
PubMed ID 8251759
Journal Protein Expr Purif
Year 1993
Volume 4
Pages 473-8
Authors Hernandez D, Phillips AT
Title Purification and characterization of Pseudomonas putida histidine ammonia-lyase expressed in Escherichia coli.
Related PDB
Related UniProtKB
[6]
Resource
Comments ACTIVE SITE, AND MUTAGENESIS.
Medline ID 94296420
PubMed ID 8024588
Journal Biochem Biophys Res Commun
Year 1994
Volume 201
Pages 1433-8
Authors Hernandez D, Phillips AT
Title Ser-143 is an essential active site residue in histidine ammonia-lyase of Pseudomonas putida.
Related PDB
Related UniProtKB P21310
[7]
Resource
Comments ACTIVE SITE, AND MUTAGENESIS.
Medline ID 94263952
PubMed ID 8204579
Journal Biochemistry
Year 1994
Volume 33
Pages 6462-7
Authors Langer M, Reck G, Reed J, Retey J
Title 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.
Related PDB
Related UniProtKB P21310
[8]
Resource
Comments
Medline ID
PubMed ID 8947915
Journal Naturwissenschaften
Year 1996
Volume 83
Pages 439-47
Authors Retey J
Title Enzymatic catalysis by Friedel-Crafts-type reactions.
Related PDB
Related UniProtKB
[9]
Resource
Comments
Medline ID
PubMed ID 9761874
Journal Acta Crystallogr D Biol Crystallogr
Year 1998
Volume 54
Pages 681-3
Authors Teo B, Kidd RD, Mack J, Tiwari A, Hernandez D, Phillips AT, Farber GK
Title Crystallization and preliminary X-ray studies of Pseudomonas putida histidine ammonium-lyase.
Related PDB
Related UniProtKB
[10]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS), AND REVISIONS TO 151 AND 438.
Medline ID 99238310
PubMed ID 10220322
Journal Biochemistry
Year 1999
Volume 38
Pages 5355-61
Authors Schwede TF, Retey J, Schulz GE
Title Crystal structure of histidine ammonia-lyase revealing a novel polypeptide modification as the catalytic electrophile.
Related PDB 1b8f
Related UniProtKB P21310
[11]
Resource
Comments
Medline ID
PubMed ID 10195286
Journal Protein Eng
Year 1999
Volume 12
Pages 151-3
Authors Schwede TF, Badeker M, Langer M, Retey J, Schulz GE
Title Homogenization and crystallization of histidine ammonia-lyase by exchange of a surface cysteine residue.
Related PDB
Related UniProtKB
[12]
Resource
Comments
Medline ID
PubMed ID 11665488
Journal Adv Protein Chem
Year 2001
Volume 58
Pages 175-214
Authors Langer B, Langer M, Retey J
Title Methylidene-imidazolone (MIO) from histidine and phenylalanine ammonia-lyase.
Related PDB
Related UniProtKB
[13]
Resource
Comments
Medline ID
PubMed ID 11578924
Journal Curr Opin Chem Biol
Year 2001
Volume 5
Pages 512-24
Authors Poppe L
Title Methylidene-imidazolone: a novel electrophile for substrate activation.
Related PDB
Related UniProtKB
[14]
Resource
Comments
Medline ID
PubMed ID 11732994
Journal Eur J Biochem
Year 2001
Volume 268
Pages 6011-9
Authors Rother D, Poppe L, Viergutz S, Langer B, Retey J
Title Characterization of the active site of histidine ammonia-lyase from Pseudomonas putida.
Related PDB
Related UniProtKB
[15]
Resource
Comments
Medline ID
PubMed ID 11457276
Journal J Am Chem Soc
Year 2001
Volume 123
Pages 4679-86
Authors Donnelly M, Fedeles F, Wirstam M, Siegbahn PE, Zimmer M
Title Computational analysis of the autocatalytic posttranslational cyclization observed in histidine ammonia-lyase. A comparison with green fluorescent protein.
Related PDB
Related UniProtKB
[16]
Resource
Comments
Medline ID
PubMed ID 11895450
Journal Eur J Biochem
Year 2002
Volume 269
Pages 1790-7
Authors Baedeker M, Schulz GE
Title Structures of two histidine ammonia-lyase modifications and implications for the catalytic mechanism.
Related PDB 1gkj 1gkm
Related UniProtKB
[17]
Resource
Comments Homologous enzyme
Medline ID
PubMed ID 12071972
Journal Eur J Biochem
Year 2002
Volume 269
Pages 3065-75
Authors Rother D, Poppe L, Morlock G, Viergutz S, Retey J
Title An active site homology model of phenylalanine ammonia-lyase from Petroselinum crispum.
Related PDB
Related UniProtKB
[18]
Resource
Comments
Medline ID
PubMed ID 11796111
Journal Structure (Camb)
Year 2002
Volume 10
Pages 61-7
Authors Baedeker M, Schulz GE
Title Autocatalytic peptide cyclization during chain folding of histidine ammonia-lyase.
Related PDB 1eb4 1gk2 1gk3
Related UniProtKB

Comments
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]).

Created Updated
2004-06-09 2009-02-26