4-Hydroxybutyrate dehydrogenase

4-Hydroxybutyrate dehydrogenase

Crystal structure of 4-Hydroxybutyrate dehydrogenase

4-Hydroxybutyrate dehydrogenase is an enzyme that catalyzes the oxidation of 4-hydroxybutyrate to succinate semialdehyde. This enzyme is part of the metabolic pathway involved in the degradation of gamma-hydroxybutyrate (GHB), a naturally occurring neurotransmitter and psychoactive drug.

Function

4-Hydroxybutyrate dehydrogenase plays a crucial role in the metabolism of GHB. It facilitates the conversion of 4-hydroxybutyrate, a metabolite of GHB, into succinate semialdehyde, which is then further oxidized to succinate, entering the citric acid cycle. This process is essential for the detoxification and clearance of GHB from the body.

Structure

The enzyme is a member of the short-chain dehydrogenase/reductase (SDR) family. It typically functions as a homodimer, with each subunit contributing to the active site. The crystal structure of 4-Hydroxybutyrate dehydrogenase, as shown in the image, reveals a typical SDR fold with a central beta-sheet flanked by alpha-helices.

Mechanism

The catalytic mechanism of 4-Hydroxybutyrate dehydrogenase involves the transfer of a hydride ion from the substrate to the cofactor NAD+, reducing it to NADH. This reaction is facilitated by a conserved tyrosine residue in the active site, which acts as a proton donor.

Clinical significance

Deficiency or malfunction of 4-Hydroxybutyrate dehydrogenase can lead to the accumulation of GHB, which may result in neurological symptoms due to its action as a central nervous system depressant. Understanding the function and regulation of this enzyme is important for developing treatments for conditions associated with GHB metabolism.

Related pages

• Gamma-Hydroxybutyrate
• Citric acid cycle
• Short-chain dehydrogenase/reductase