BDH1 (Q02338) review notes

Gene identity

D-beta-hydroxybutyrate dehydrogenase, mitochondrial (BDH; SDR9C1). HGNC:1027, EC 1.1.1.30.
Member of the short-chain dehydrogenase/reductase (SDR) family; NAD(P)-binding Rossmann fold
[file:human/BDH1/BDH1-uniprot.txt "Belongs to the short-chain dehydrogenases/reductases (SDR) family"].
343 aa precursor; N-terminal mitochondrial transit peptide 1..46; mature chain 47..343
[file:human/BDH1/BDH1-uniprot.txt TRANSIT 1..46; CHAIN 47..343].

NAD+-dependent D-beta-hydroxybutyrate dehydrogenase catalysing the reversible interconversion
of the two ketone bodies: (R)-3-hydroxybutanoate + NAD+ ⇌ acetoacetate + NADH + H+
[file:human/BDH1/BDH1-uniprot.txt "Reaction=(R)-3-hydroxybutanoate + NAD(+) = acetoacetate + NADH + H(+)"; EC=1.1.1.30].
Terminal step of ketogenesis (making beta-hydroxybutyrate, the main circulating ketone) and the
first step of ketolysis (regenerating acetoacetate in peripheral tissues). Reactome represents
both directions: R-HSA-73912 (acetoacetate + NADH -> BHB, synthesis direction) and
R-HSA-73920 (BHB + NAD+ -> acetoacetate, utilization direction). UniProt DR: Reactome
R-HSA-77108 Utilization of Ketone Bodies; R-HSA-77111 Synthesis of Ketone Bodies.
Lipid-dependent enzyme: requires phosphatidylcholine as an allosteric activator
[file:human/BDH1/BDH1-uniprot.txt "Requires phosphatidylcholine as an allosteric"]
PMID:8679568.
Homotetramer [file:human/BDH1/BDH1-uniprot.txt "Homotetramer"].
Localization: mitochondrion inner membrane / matrix side; also detected in matrix
[file:human/BDH1/BDH1-uniprot.txt "Mitochondrion inner membrane"].

PMID:8679568 (Green et al. 1996, Biochemistry): expressed mature human heart BDH in Sf9 insect
cells; catalytically active, Km for NAD+ and (R)-3-hydroxybutyrate similar to native enzyme;
PC requirement confirmed; C-terminal region required for catalysis/lipid binding. Supports the
IDA for GO:0003858 3-hydroxybutyrate dehydrogenase activity (abstract-only cache; full text read
by curator).
PMID:34800366 (MitoCoP, Cell Metab 2021): high-confidence human mitochondrial proteome (1,134
genes); supports HTP mitochondrion localization.

Core MF: GO:0003858 3-hydroxybutyrate dehydrogenase activity (IBA + IEA-RHEA/EC + IDA) -> ACCEPT.
GO:0016616 (oxidoreductase acting on CH-OH, NAD/NADP acceptor) is a direct parent of GO:0003858;
ARBA IEA is not wrong but is redundant/less informative -> MARK_AS_OVER_ANNOTATED.
Ketone-body processes: the Ensembl IEA terms GO:0042181 "ketone biosynthetic process" and
GO:0042182 "ketone catabolic process" are more general than the ketone-BODY-specific terms.
BDH1 acts specifically on the ketone body beta-hydroxybutyrate/acetoacetate, so MODIFY to
GO:0046951 ketone body biosynthetic process and GO:0046952 ketone body catabolic process.
(Note GO:1902224 "ketone body metabolic process" is OBSOLETE, verified via QuickGO 2026-07.)
Locations: mitochondrial inner membrane (IBA/IEA/ISS), matrix side of inner membrane (ISS,
most precise), matrix (IEA/ISS/TAS), mitochondrion (HTP) -> all ACCEPT (inner-membrane-anchored,
matrix-facing active site).
Reactome CLPXP TAS rows (R-HSA-9838035 binds, R-HSA-9838289 degrades): these place BDH1 in the
matrix as a generic CLPXP protease substrate, not a BDH1-specific function. The matrix
localization is fine; keep as non-core.

GO:0003858 3-hydroxybutyrate dehydrogenase activity (MF, current)
GO:0005743 mitochondrial inner membrane (CC, current)
GO:0005759 mitochondrial matrix (CC, current)
GO:0016616 oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor (MF)
GO:0046951 ketone body biosynthetic process (BP, current)
GO:0046952 ketone body catabolic process (BP, current)
GO:0099617 matrix side of mitochondrial inner membrane (CC, current)
GO:0005739 mitochondrion (CC, current)
GO:0051287 NAD binding (MF, current)