PDBsum entry 3ewc

Hydrolase

PDB id: 3ewc

Contents

Protein chain

357 a.a. *

Ligands

MCF

Metals

_ZN

Waters ×64

* Residue conservation analysis

PDB id:

3ewc

Name:

Hydrolase

Title:

Crystal structure of adenosine deaminase from plasmodial vivax in complex with mt-coformycin

Structure:

Adenosine deaminase. Chain: a. Engineered: yes

Source:

Plasmodium vivax. Organism_taxid: 5855. Gene: pvx_111245. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.11Å R-factor: 0.204 R-free: 0.254

Authors:

V.L.Schramm,S.C.Almo,M.B.Cassera,M.C.Ho

Key ref:

M.C.Ho et al. (2009). Structural and metabolic specificity of methylthiocoformycin for malarial adenosine deaminases. Biochemistry, 48, 9618-9626. PubMed id: 19728741

Date:

14-Oct-08 Release date: 22-Sep-09

Protein chain

A5KE01  (A5KE01_PLAVS) -  Adenosine deaminase from Plasmodium vivax (strain Salvador I)

Seq: 363 a.a.

Struc: 357 a.a.

Enzyme reactions

• Enzyme class 1: E.C.3.5.4.31 - S-methyl-5'-thioadenosine deaminase.
• Reaction: S-methyl-5'-thioadenosine + H2O + H⁺ = S-methyl-5'-thioinosine + NH4⁺

S-methyl-5'-thioadenosine + H2O + H(+) (Bound ligand (Het Group name = MCF) matches with 70.83% similarity) = S-methyl-5'-thioinosine + NH4(+)

• Enzyme class 2: E.C.3.5.4.4 - adenosine deaminase.
• Reaction:
  1. adenosine + H2O + H⁺ = inosine + NH4⁺
  2. 2'-deoxyadenosine + H2O + H⁺ = 2'-deoxyinosine + NH4⁺

adenosine (Bound ligand (Het Group name = MCF) matches with 73.91% similarity) + H2O + H(+) = inosine + NH4(+)

2'-deoxyadenosine (Bound ligand (Het Group name = MCF) matches with 69.57% similarity) + H2O + H(+) = 2'-deoxyinosine + NH4(+)

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

Biochemistry 48:9618-9626 (2009)

PubMed id: 19728741

Structural and metabolic specificity of methylthiocoformycin for malarial adenosine deaminases.

M.C.Ho, M.B.Cassera, D.C.Madrid, L.M.Ting, P.C.Tyler, K.Kim, S.C.Almo, V.L.Schramm.

ABSTRACT

Plasmodium falciparum is a purine auxotroph requiring hypoxanthine as a key metabolic precursor. Erythrocyte adenine nucleotides are the source of the purine precursors, making adenosine deaminase (ADA) a key enzyme in the pathway of hypoxanthine formation. Methylthioadenosine (MTA) is a substrate for most malarial ADAs, but not for human ADA. The catalytic site specificity of malarial ADAs permits methylthiocoformycin (MT-coformycin) to act as a Plasmodium-specific transition state analogue with low affinity for human ADA [Tyler, P. C., Taylor, E. A., Frohlich, R. G. G., and Schramm, V. L. (2007) J. Am. Chem. Soc. 129, 6872-6879]. The structural basis for MTA and MT-coformycin specificity in malarial ADAs is the subject of speculation [Larson, E. T., et al. (2008) J. Mol. Biol. 381, 975-988]. Here, the crystal structure of ADA from Plasmodium vivax (PvADA) in a complex with MT-coformycin reveals an unprecedented binding geometry for 5'-methylthioribosyl groups in the malarial ADAs. Compared to malarial ADA complexes with adenosine or deoxycoformycin, 5'-methylthioribosyl groups are rotated 130 degrees . A hydrogen bonding network between Asp172 and the 3'-hydroxyl of MT-coformycin is essential for recognition of the 5'-methylthioribosyl group. Water occupies the 5'-hydroxyl binding site when MT-coformycin is bound. Mutagenesis of Asp172 destroys the substrate specificity for MTA and MT-coformycin. Kinetic, mutagenic, and structural analyses of PvADA and kinetic analysis of five other Plasmodium ADAs establish the unique structural basis for its specificity for MTA and MT-coformycin. Plasmodium gallinaceum ADA does not use MTA as a substrate, is not inhibited by MT-coformycin, and is missing Asp172. Treatment of P. falciparum cultures with coformycin or MT-coformycin in the presence of MTA is effective in inhibiting parasite growth.