page_title: Homoserine dehydrogenase
section_title: Enzyme mechanism
hierarchical_section_title: Homoserine dehydrogenase / Enzyme mechanism
caption_attribution_description: English: Hypothesized hydride transfer reaction mechanism catalyzed by homoserine dehydrogenase and NAD(P)H.
context_page_description: In enzymology, a homoserine dehydrogenase is an enzyme that catalyzes the chemical reaction
  L-homoserine + NAD⁺ L-aspartate 4-semialdehyde + NADH + H⁺
  The 2 substrates of this enzyme are L-homoserine and NAD⁺, whereas its 3 products are L-aspartate 4-semialdehyde, NADH, and H⁺.
  This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-OH group of donor with NAD⁺ or NADP⁺ as acceptor. The systematic name of this enzyme class is L-homoserine:NAD⁺ oxidoreductase. Other names in common use include HSDH, and HSD.
  Homoserine dehydrogenase catalyses the third step in the aspartate pathway; the NAD-dependent reduction of aspartate beta-semialdehyde into homoserine. Homoserine is an intermediate in the biosynthesis of threonine, isoleucine, and methionine.
context_section_description: Homoserine dehydrogenase catalyzes the reaction of aspartate-semialdehyde (ASA) to homoserine. The overall reaction reduces the C4 carboxylic acid functional group of ASA to a primary alcohol and oxidizes the C1 aldehyde to a carboxylic acid. Residues Glu 208 and Lys 117 are thought to be involved in the active catalytic site of the enzyme. Asp 214 and Lys 223 have been shown to be important for hydride transfer in the catalyzed reaction.
  Once the C4 carboxylic acid is reduced to an aldehyde and the C1 aldehyde is oxidized to a carboxylic acid, experiments suggest that Asp 219, Glu 208 and a water molecule bind ASA in the active site while Lys 223 donates a proton to the aspartate-semialdehyde C4 oxygen. Homoserine dehydrogenase has an NAD(P)H cofactor, which then donates a hydrogen to the same carbon, effectively reducing the aldehyde to an alcohol. (Refer to figures 1 and 2).
  However, the precise mechanism of complete homoserine dehydrogenase catalysis remains unknown.
  The homoserine dehydrogenase-catalyzed reaction has been postulated to proceed through a bi-bi kinetic mechanism, where the NAD(P)H cofactor binds the enzyme first and is the last to dissociate from the enzyme once the reaction is complete. Additionally, while both NADH and NADPH are adequate cofactors for the reaction, NADH is preferred. The Kₘ of the reaction is four-times smaller with NADH and the Kcat/Kₘ is three-times greater, indicating a more efficient reaction.
  Homoserine dehydrogenase also exhibits multi-order kinetics at subsaturating levels of substrate. Additionally, the variable kinetics for homoserine dehydrogenase is an artifact of the faster dissociation of the amino acid substrate from the enzyme complex as compared to cofactor dissociation.
caption: Figure 1. Hypothesized hydride transfer reaction mechanism catalyzed by homoserine dehydrogenase and NAD(P)H.
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