3-dehydroquinate dehydratase (type II)

 

3-Dehydroquinate dehydratase catalyses the dehydration of 3-dehydroquinate to 3-dehydroshikimate. This reaction is part of both the biosynthetic shikimate pathway for organic compound synthesis and the catabolic quinate pathway using quinate as an energy and carbon source. These pathways are both absent in animals. Type I and type II dehydroquinases exist, with completely different mechanisms and sequences, and this enzyme in question is part of the latter class. The existence of two types allows the targeting of drugs for type II to be developed.

 

Reference Protein and Structure

Sequence
P15474 UniProt (4.2.1.10) IPR001874 (Sequence Homologues) (PDB Homologues)
Biological species
Streptomyces coelicolor A3(2) (Bacteria) Uniprot
PDB
1gu1 - Crystal structure of type II dehydroquinase from Streptomyces coelicolor complexed with 2,3-anhydro-quinic acid (1.8 Å) PDBe PDBsum 1gu1
Catalytic CATH Domains
3.40.50.9100 CATHdb (see all for 1gu1)
Cofactors
Water (1)
Click To Show Structure

Enzyme Reaction (EC:4.2.1.10)

3-dehydroquinate
CHEBI:32364ChEBI
→
water
CHEBI:15377ChEBI
+
3-dehydroshikimate
CHEBI:16630ChEBI
Alternative enzyme names: 3-dehydroquinase, 3-dehydroquinate hydrolase, 5-dehydroquinase, 5-dehydroquinate dehydratase, 5-dehydroquinate hydro-lyase, DHQase, Dehydroquinase, Dehydroquinate dehydratase, 3-dehydroquinate hydro-lyase,

Enzyme Mechanism

Introduction

3-Dehydroquinate dehydratase catalyses a trans-dehydration via an enolate intermediate. Tyr 28 acts as a general base catalyst in abstracting a proton from C2, and is assisted by having its pKa lowered by Arg 23 and Arg 113. A water molecule activated by Asn 16 is deprotonated, and protonated by Asn 16 acting as a general acid catalyst. A water molecule is then activated by Asn 16 acting as a general base catalyst to deprotonate C1 and cause loss of a water molecule from the C3 hydroxyl position by His 106 acting as a general acid catalyst. It is activated by Glu 104 through a hydrogen bonding arrangement. Release of the product follows.

Catalytic Residues Roles

UniProt PDB* (1gu1)
Glu105 Glu104A Activates His 106. hydrogen bond acceptor, hydrogen bond donor, proton acceptor, proton donor
Asn17 Asn16A Acts as a general acid/base catalyst to activate water in proton donation and abstraction. hydrogen bond acceptor, hydrogen bond donor, proton acceptor, proton donor
Ala83 (main-N), Pro16 (main-C), Asn17 Ala82A (main-N), Pro15A (main-C), Asn16A Hold a water molecule in place so that it can act as an electrostatic stabiliser. activator, hydrogen bond donor, steric role
Tyr29 Tyr28A Acts as a general base catalyst in deprotonation of the substrate at the C2 position. hydrogen bond acceptor, hydrogen bond donor, proton acceptor, proton donor
His107 His106A Acts as a general acid catalyst in donation of a proton to the substrate to form water in a condensation reaction. hydrogen bond acceptor, hydrogen bond donor, proton acceptor, proton donor, proton relay
Asn80 Asn79A Helps stabilise the reaction intermediates. hydrogen bond acceptor, steric role
Arg24, Arg114 Arg23A, Arg113A Activates Tyr 28 by lowering its pKa. attractive charge-charge interaction, activator, electrostatic stabiliser, polar interaction
*PDB label guide - RESx(y)B(C) - RES: Residue Name; x: Residue ID in PDB file; y: Residue ID in PDB sequence if different from PDB file; B: PDB Chain; C: Biological Assembly Chain if different from PDB. If label is "Not Found" it means this residue is not found in the reference PDB.

Chemical Components

proton transfer, assisted keto-enol tautomerisation, intermediate formation, overall reactant used, proton relay, bimolecular elimination, overall product formed, intermediate terminated, intermediate collapse, dehydration, native state of enzyme regenerated, inferred reaction step

References

  1. Roszak AW et al. (2002), Structure, 10, 493-503. The Structure and Mechanism of the Type II Dehydroquinase from Streptomyces coelicolor. DOI:10.1016/s0969-2126(02)00747-5. PMID:11937054.
  2. Reiling S et al. (2014), Acta Crystallogr F Struct Biol Commun, 70, 1485-1491. Structure of type II dehydroquinase fromPseudomonas aeruginosa. DOI:10.1107/s2053230x14020214. PMID:25372814.
  3. Chu W et al. (2013), Mol Simul, 39, 137-144. Molecular dynamics (MD) simulations and binding free energy calculation studies between inhibitors and type II dehydroquinase (DHQ2). DOI:10.1080/08927022.2012.708416.
  4. Payne RJ et al. (2007), ChemMedChem, 2, 1010-1013. Design, Synthesis, and Structural Studies on Potent Biaryl Inhibitors of Type II Dehydroquinases. DOI:10.1002/cmdc.200700062. PMID:17487901.
  5. González-Bello C et al. (2007), Med Res Rev, 27, 177-208. Progress in type II dehydroquinase inhibitors: From concept to practice. DOI:10.1002/med.20076. PMID:17004270.
  6. Robinson DA et al. (2006), J Med Chem, 49, 1282-1290. Crystal Structures ofHelicobacterpyloriType II Dehydroquinase Inhibitor Complexes:  New Directions for Inhibitor Design. DOI:10.1021/jm0505361. PMID:16480265.
  7. Toscano MD et al. (2005), Org Biomol Chem, 3, 3102-3104. Rational design of new bifunctional inhibitors of type II dehydroquinase. DOI:10.1039/b507156a. PMID:16106291.
  8. Frederickson M et al. (2004), Org Biomol Chem, 2, 1592-1596. (1R,4S,5R)-3-Fluoro-1,4,5-trihydroxy-2-cyclohexene-1-carboxylic acid: the fluoro analogue of the enolate intermediate in the reaction catalyzed by type II dehydroquinases. DOI:10.1039/b404535a. PMID:15162210.
  9. Maes D et al. (2004), Acta Crystallogr D Biol Crystallogr, 60, 463-471. Structural study of the type II 3-dehydroquinate dehydratase fromActinobacillus pleuropneumoniae. DOI:10.1107/s090744490302969x. PMID:14993670.
  10. Lee BI et al. (2003), Proteins, 51, 616-617. Crystal structure of the type II 3-dehydroquinase from Helicobacter pylori. DOI:10.1002/prot.10415. PMID:12784220.
  11. Gourley DG et al. (1999), Nat Struct Biol, 6, 521-525. The two types of 3-dehydroquinase have distinct structures but catalyze the same overall reaction. DOI:10.1038/9287. PMID:10360352.

Step 1. Tyr28 deprotonates the substrate, forming a double bond and causing the ketone group to reduce and deprotonate water, which in turn deprotonates Asn16.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Asn79A hydrogen bond acceptor
Arg113A attractive charge-charge interaction, electrostatic stabiliser
His106A hydrogen bond acceptor, hydrogen bond donor
Pro15A (main-C) hydrogen bond acceptor, activator, steric role
Asn16A hydrogen bond donor
Arg23A attractive charge-charge interaction, electrostatic stabiliser
Tyr28A hydrogen bond acceptor
Ala82A (main-N) hydrogen bond donor, activator, steric role
Glu104A hydrogen bond donor
Asn16A proton donor
Tyr28A proton acceptor

Chemical Components

proton transfer, assisted keto-enol tautomerisation, intermediate formation, overall reactant used, proton relay

Step 2. Asn16 deprotonates water, which deprotonates the C1-hydroxy, causing a double bond rearrangement that eliminates water with deprotonation of His106, which in turn deprotonates Glu104.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Asn79A hydrogen bond acceptor, steric role
Arg113A polar interaction, electrostatic stabiliser
His106A hydrogen bond acceptor, hydrogen bond donor
Pro15A (main-C) hydrogen bond acceptor, steric role, activator
Asn16A hydrogen bond acceptor
Arg23A polar interaction, electrostatic stabiliser
Ala82A (main-N) hydrogen bond donor, steric role, activator
Glu104A hydrogen bond donor
Asn16A proton acceptor
His106A proton donor
Glu104A proton donor
His106A proton acceptor, proton relay

Chemical Components

ingold: bimolecular elimination, proton transfer, overall product formed, intermediate terminated, intermediate collapse, dehydration, proton relay

Step 3. Glu104 deprotonates His106, which deprotonates water, which in turn deprotonates Tyr28 in an inferred step.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Asn79A hydrogen bond acceptor
Arg113A polar interaction, activator
His106A hydrogen bond acceptor, hydrogen bond donor
Pro15A (main-C) hydrogen bond acceptor, steric role, activator
Asn16A hydrogen bond acceptor, hydrogen bond donor
Arg23A polar interaction, activator
Tyr28A hydrogen bond donor
Ala82A (main-N) hydrogen bond donor
Glu104A hydrogen bond acceptor
His106A proton acceptor
Glu104A proton acceptor
His106A proton donor
Tyr28A proton donor
His106A proton relay

Chemical Components

proton transfer, proton relay, native state of enzyme regenerated, inferred reaction step
Download: Image, Marvin File

Step 1. Tyr28 deprotonates the substrate, forming a double bond and causing the ketone group to reduce and deprotonate water, which in turn deprotonates Asn16.

Step 2. Asn16 deprotonates water, which deprotonates the C1-hydroxy, causing a double bond rearrangement that eliminates water with deprotonation of His106, which in turn deprotonates Glu104.

Step 3. Glu104 deprotonates His106, which deprotonates water, which in turn deprotonates Tyr28 in an inferred step.

Products.

Contributors

Gemma L. Holliday, Gail J. Bartlett, Daniel E. Almonacid, Gary McDowell