Cofactors

There are no Cofactors for this Enzyme

Reaction Mechanism

homoserine dehydrogenase By Reference

Homoserine dehydrogenase belongs to the oxioreductase class of enzymes, although the residues implicated in catalysis are quite different from other enzymes within the class. It is involved in the NAD(P)H dependent reduction of L-aspartate semi-aldehyde to L homoserine, a pathway not found within the animal kingdom. The enzyme has therefore been targeted for the development of antimycotic drugs.




The NAD(P)H dependent reduction of L aspartate semi-aldehyde proceeds via hydride transfer. The hydride donating NAD(P)H cofactor is bound in the Rossmann fold, where enzyme-cofactor hydrogen bond interactions exist between cofactor phosphate moieties and sugar hydroxyl groups and the enzyme amide back bone groups. The amino substrate is thought to bind predominantly in the aldehyde rather than the hydrate form through hydrogen bond interactions with Asp 214, Glu 208, and a water molecule (460). The catalytic Lys 223 donates a proton to the developing alkoxide tetrahedral intermediate during hydride transfer. Asp 219 is key in positioning the catalytic residue, while the N terminal helix alpha J is important in stabilising the developing negative charge on the substrate carbonyl.

Catalytic Residues

AA	Uniprot	Uniprot Resid	PDB	PDB Resid
Asp	P31116	219	1ebf	218
Lys	P31116	223	1ebf	222
View Reaction Mechanisms in M-CSA

Reaction Parameters

• Kinetic Parameters

  Organism	KM Value [mM]	Substrate	Comment
  Bacillus subtilis	0.031	L-homoserine	pH 9.0, 25°C, recombinant enzyme
  Glycine max	0.039	L-homoserine	cosubstrate NADP+, pH 8.0, 25°C
  Thermus thermophilus	6.2	NAD+	pH 9.5, 50°C, recombinant enzyme
  Pyrococcus horikoshii	89.1	NADP+	pH 9.0, 50°C, recombinant mutant R40A

• Temperature

  Organism	Temperature Range	Comment
  Thermophilic bacterium	20 - 70	no activity at 80°C
  Bacillus subtilis	25 - 50	45% of maximal activity at 25°C and 50°C, maximal activity at 35-40°C, 75% at 45°C, 65% at 35°C, profile overview
  Thermotoga maritima	50 - 80	over 30% of maximal activity within this range, profile overview

• pH

  Organism	pH Range	Comment
  Thermotoga maritima	6.5 - 11	over 60% of maximal activity within this range, profile overview
  Bacillus subtilis	7 - 9.5	BsHSD is maximally active in L-HSE oxidation at pH 9.0 and is the least active at pH 7.0 with only 1.1% of the maximal activity
  Thermophilic bacterium	8 - 10

Associated Proteins

Citations

• Heterologous overexpression and characterization of homoserine dehydrogenase from Paracoccidioides brasiliensis.
• Virtual screening and repurposing of approved drugs targeting homoserine dehydrogenase from Paracoccidioides brasiliensis.
• Conformational changes in the catalytic region are responsible for heat-induced activation of hyperthermophilic homoserine dehydrogenase.
• Molecular and Enzymatic Features of Homoserine Dehydrogenase from Bacillus subtilis.
• Expression, purification, and biochemical characterization of an NAD⁺-dependent homoserine dehydrogenase from the symbiotic Polynucleobacter necessarius subsp. necessarius.
• Characterization of a Novel Type Homoserine Dehydrogenase Only with High Oxidation Activity from Arthrobacter nicotinovorans
• Biochemical characterization and redesign of the coenzyme specificity of a novel monofunctional NAD⁺-dependent homoserine dehydrogenase from the human pathogen Neisseria gonorrhoeae.
• New inhibitors of homoserine dehydrogenase from Paracoccidioides brasiliensis presenting antifungal activity.
• The crystal structure of homoserine dehydrogenase complexed with l-homoserine and NADPH in a closed form.
• Antifungal dipeptides incorporating an inhibitor of homoserine dehydrogenase.
• Inhibition of homoserine dehydrogenase by formation of a cysteine-NAD covalent complex.