PDBsum entry 6aym

Hydrolase, transferase

PDB id: 6aym

Contents

Protein chains

229 a.a.

Ligands

EDO ×9

Waters ×593

PDB id:

6aym

Name:

Hydrolase, transferase

Title:

Crystal structure of campylobacter jejuni 5'-methylthioadenosine/s- adenosyl homocysteine nucleosidase (mtan)

Structure:

5'-methylthioadenosine/s-adenosylhomocysteine nucleosidase. Chain: a, b. Engineered: yes

Source:

Campylobacter jejuni. Organism_taxid: 197. Gene: a0m70_07260, ajy53_05400. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.25Å R-factor: 0.190 R-free: 0.205

Authors:

R.K.Harijan,R.G.Ducati,J.B.Bonanno,S.C.Almo,V.L.Schramm

Key ref:

R.G.Ducati et al. (2018). Transition-State Analogues of Campylobacter jejuni 5'-Methylthioadenosine Nucleosidase. ACS Chem Biol, 13, 3173-3183. PubMed id: 30339406 DOI: 10.1021/acschembio.8b00781

Date:

08-Sep-17 Release date: 12-Sep-18

Protein chains

Q0PC20  (MQMTN_CAMJE) -  Aminodeoxyfutalosine nucleosidase from Campylobacter jejuni subsp. jejuni serotype O:2 (strain ATCC 700819 / NCTC 11168)

Seq: 229 a.a.

Struc: 229 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class 2: E.C.3.2.2.30 - aminodeoxyfutalosine nucleosidase.
• Reaction: 6-amino-6-deoxyfutalosine + H2O = dehypoxanthine futalosine + adenine
• Enzyme class 3: E.C.3.2.2.9 - adenosylhomocysteine nucleosidase.

Pathway:

• Reaction:
  1. S-adenosyl-L-homocysteine + H2O = S-(5-deoxy-D-ribos-5-yl)-L- homocysteine + adenine
  2. 5'-deoxyadenosine + H2O = 5-deoxy-D-ribose + adenine
  3. S-methyl-5'-thioadenosine + H2O = 5-(methylsulfanyl)-D-ribose + adenine

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/acschembio.8b00781

ACS Chem Biol 13:3173-3183 (2018)

PubMed id: 30339406

Transition-State Analogues of Campylobacter jejuni 5'-Methylthioadenosine Nucleosidase.

R.G.Ducati, R.K.Harijan, S.A.Cameron, P.C.Tyler, G.B.Evans, V.L.Schramm.

ABSTRACT

Campylobacter jejuni is a Gram-negative bacterium responsible for food-borne gastroenteritis and associated with Guillain-Barré, Reiter, and irritable bowel syndromes. Antibiotic resistance in C. jejuni is common, creating a need for antibiotics with novel mechanisms of action. Menaquinone biosynthesis in C. jejuni uses the rare futalosine pathway, where 5'-methylthioadenosine nucleosidase ( CjMTAN) is proposed to catalyze the essential hydrolysis of adenine from 6-amino-6-deoxyfutalosine to form dehypoxanthinylfutalosine, a menaquinone precursor. The substrate specificity of CjMTAN is demonstrated to include 6-amino-6-deoxyfutalosine, 5'-methylthioadenosine, S-adenosylhomocysteine, adenosine, and 5'-deoxyadenosine. These activities span the catalytic specificities for the role of bacterial MTANs in menaquinone synthesis, quorum sensing, and S-adenosylmethionine recycling. We determined inhibition constants for potential transition-state analogues of CjMTAN. The best of these compounds have picomolar dissociation constants and were slow-onset tight-binding inhibitors. The most potent CjMTAN transition-state analogue inhibitors inhibited C. jejuni growth in culture at low micromolar concentrations, similar to gentamicin. The crystal structure of apoenzyme C. jejuni MTAN was solved at 1.25 Å, and five CjMTAN complexes with transition-state analogues were solved at 1.42 to 1.95 Å resolution. Inhibitor binding induces a loop movement to create a closed catalytic site with Asp196 and Ile152 providing purine leaving group activation and Arg192 and Glu12 activating the water nucleophile. With inhibitors bound, the interactions of the 4'-alkylthio or 4'-alkyl groups of this inhibitor family differ from the Escherichia coli MTAN structure by altered protein interactions near the hydrophobic pocket that stabilizes 4'-substituents of transition-state analogues. These CjMTAN inhibitors have potential as specific antibiotic candidates against C. jejuni.