An in silico analysis of the glutamate dehydrogenases of Teladorsagia circumcincta and Haemonchus contortus

Abstract

Nematode glutamate dehydrogenase (GDH) amino acid sequences are very highly conserved (68-99% identity) and are also very similar to those of the bovine and human enzymes (54-60% identity). The residues involved in binding nucleotides or substrates are completely conserved and tend to be located in highly conserved regions of the sequence. Based on the strong homology between the bovine, Teladorsagia circumcincta and Haemonchus contortus GDH sequences, models of the structure of the T. circumcincta and H. contortus monomers were constructed. The structure of the T. circumcincta monomer obtained using SWISS-MODEL was very similar to that of the bovine enzyme monomer and the backbone of the polypetide deviated very little from that of the bovine enzyme monomer. Despite the sequence differences between the bovine and T. circumcincta enzymes, the relative positions and orientations of the residues involved in ligand binding were very similar. The reported Km for NADP+ of T. circumcincta is about 35 and times that of the bovine enzyme, whereas the Kms of the two enzymes for glutamate, α-ketoglutarate and NAD(P)H are much more similar. The residue corresponding to S267 of the bovine enzyme is involved in binding the 2'-phosphate of NADP+ and is replaced in the T. circumcincta and H. contortus sequences by a tryptophan. The partial occlusion of the NAD(P)-binding site by the tryptophan sidechain and the loss of at least one potential H-bond provided by the serine may explain the lower affinity of the T. circumcincta for NADP+