Mechanism of action and NAD ⁺ -binding mode revealed by the crystal structure of l -histidinol dehydrogenase

Abstract

The histidine biosynthetic pathway is an ancient one found in bacteria, archaebacteria, fungi, and plants that converts 5-phosphoribosyl 1-pyrophosphate to L-histidine in 10 enzymatic reactions. This pathway provided a paradigm for the operon, transcriptional regulation of gene expression, and feedback inhibition of a pathway. L-histidinol dehydrogenase (HisD, EC 1.1.1.23) catalyzes the last two steps in the biosynthesis of L-histidine: sequential NAD-dependent oxidations of L-histidinol to L-histidinaldehyde and then to L-histidine. HisD functions as a homodimer and requires the presence of one Zn 2؉ cation per monomer. We have determined the three-dimensional structure of Escherichia coli HisD in the apo state as well as complexes with substrate, Zn 2؉ , and NAD ؉ (best resolution is 1.7 Å). Each monomer is made of four domains, whereas the intertwined dimer possibly results from domain swapping. Two domains display a very similar incomplete Rossmann fold that suggests an ancient event of gene duplication. Residues from both monomers form the active site. Zn 2؉ plays a crucial role in substrate binding but is not directly involved in catalysis. The active site residue His-327 participates in acid-base catalysis, whereas Glu-326 activates a water molecule. NAD ؉ binds weakly to one of the Rossmann fold domains in a manner different from that previously observed for other proteins having a Rossmann fold.

Diversity of the trifunctional histidine biosynthesis gene (his) in cerealPhaeosphaeriaspecies

“…None of the 5 amino acid substitutions (residues 697, 724, 731, 732, and 734) occurring in the conserved HDH sub-domain were associated with catalytic activity (Fig. 2) (Grubmeyer and Gray 1986;Teng et al 1993;Barbosa et al 2002). There were also intraspecific amino acid substitutions found in PN-w, Paa, Pat2, and P-rye ( Table 3).…”

“…The amino acids subject to forming hydrogen bonds with the substrate L-histidinol (778, 818, and 865, equivalent to H-327, H-367, and E-414 in S. typhimurium HDH) and those interacting with a Zn 2+ cation (708, 711, 811, and 870, equivalent to Q-259, H-262, D-360, and H-419 in S. typhimurium HDH) are also conserved in the PN-w HDH sub-domain (Fig. 2) (Barbosa et al 2002).…”

“…No. AAL20976) and the his genes of other ascomycetes (Donahue et al 1982;Bruni et al 1986;Grubmeyer et al 1989;Barbosa et al 2002;Wood et al 2002) (Fig. 2).…”

A role for biosynthetic CdS quantum dots in extracellular electron transfer of Saccharomyces cerevisiae

“…L-histidinol + 2NAD + +H2O→ L-histidine + 2NADH + 2H + (2) It belongs to the family of oxidoreductases, which act on the CH-OH group with NAD + or NADP + as acceptor [21,22]. Mitochondrial Aldehyde dehydrogenase (Ald6, spot 13) from S. cerevisiae is the protein responsible for rapidly oxidizing acetaldehyde [23].…”

Zinc metalloenzymes as new targets against the bacterial pathogen Brucella

“…Docking studies were carried out with compound 34i and 40a on E. coli HDH, consecutive to the proof of the very high similarity of this enzyme with B. suis HDH. E. coli HDH structure was solved after co-crystallization with NAD + and histidine [56].…”