PDBsum entry 4plz

Oxidoreductase

PDB id: 4plz

Contents

Protein chain

302 a.a.

Ligands

OXM

NAI

Waters ×547

PDB id:

4plz

Name:

Oxidoreductase

Title:

Crystal structure of plasmodium falciparum lactate dehydrogenase mutant w107fa.

Structure:

L-lactate dehydrogenase. Chain: a. Synonym: lactate dehydrogenase. Engineered: yes

Source:

Plasmodium falciparum. Organism_taxid: 5833. Gene: ldh-p, ldh, ldh. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.05Å R-factor: 0.130 R-free: 0.146

Authors:

J.I.Boucher,J.R.Jacobowitz,B.C.Beckett,S.Classen,D.L.Theobald

Key ref:

J.I.Boucher et al. (2014). An atomic-resolution view of neofunctionalization in the evolution of apicomplexan lactate dehydrogenases. Elife, 3, e02304. PubMed id: 24966208 DOI: 10.7554/eLife.02304

Date:

20-May-14 Release date: 02-Jul-14

Protein chain

Q27743  (LDH_PLAFD) -  L-lactate dehydrogenase from Plasmodium falciparum (isolate CDC / Honduras)

Seq: 316 a.a.

Struc: 302 a.a.

Enzyme reactions

• Enzyme class: E.C.1.1.1.27 - L-lactate dehydrogenase.
• Reaction: (S)-lactate + NAD⁺ = pyruvate + NADH + H⁺

(S)-lactate (Bound ligand (Het Group name = OXM) matches with 71.43% similarity) + NAD(+) (Bound ligand (Het Group name = NAI) corresponds exactly) = pyruvate + NADH + H(+)

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

reference

DOI no: 10.7554/eLife.02304

Elife 3:e02304 (2014)

PubMed id: 24966208

An atomic-resolution view of neofunctionalization in the evolution of apicomplexan lactate dehydrogenases.

J.I.Boucher, J.R.Jacobowitz, B.C.Beckett, S.Classen, D.L.Theobald.

ABSTRACT

Malate and lactate dehydrogenases (MDH and LDH) are homologous, core metabolic enzymes that share a fold and catalytic mechanism yet possess strict specificity for their substrates. In the Apicomplexa, convergent evolution of an unusual LDH from MDH produced a difference in specificity exceeding 12 orders of magnitude. The mechanisms responsible for this extraordinary functional shift are currently unknown. Using ancestral protein resurrection, we find that specificity evolved in apicomplexan LDHs by classic neofunctionalization characterized by long-range epistasis, a promiscuous intermediate, and few gain-of-function mutations of large effect. In canonical MDHs and LDHs, a single residue in the active-site loop governs substrate specificity: Arg102 in MDHs and Gln102 in LDHs. During the evolution of the apicomplexan LDH, however, specificity switched via an insertion that shifted the position and identity of this 'specificity residue' to Trp107f. Residues far from the active site also determine specificity, as shown by the crystal structures of three ancestral proteins bracketing the key duplication event. This work provides an unprecedented atomic-resolution view of evolutionary trajectories creating a nascent enzymatic function.