HSD17B10 (Q99714) review notes

Human 17-beta-hydroxysteroid dehydrogenase type 10. UniProt RecName is
"3-hydroxyacyl-CoA dehydrogenase type-2". Aliases: HADH2, MRPP2, SCHAD, SDR5C1,
ERAB, ABAD, XH98G2. HGNC:4800; Gene ID 3028; X-linked (Xp11.22). 261 aa, homotetramer.

Summary of biology (a genuinely moonlighting/multifunctional protein)

HSD17B10 has two distinct, essential roles that are functionally independent
(the disease impairs both):

  1. Catalytic (metabolic) NAD+-dependent dehydrogenase of the SDR family.
  2. Physiologically the key activity is (S)-2-methyl-3-hydroxybutyryl-CoA
    dehydrogenase (MHBD)     in L-isoleucine catabolism — oxidizes
    (2S,3S)-3-hydroxy-2-methylbutanoyl-CoA to 2-methyl-3-oxobutanoyl-CoA
    (EC 1.1.1.178; GO:0047015). Deficiency causes the "2-methyl-3-hydroxybutyryl-CoA
    dehydrogenase (MHBD) deficiency" organic aciduria
    PMID:20077426.
  3. Broad (S)-3-hydroxyacyl-CoA dehydrogenase activity (EC 1.1.1.35; GO:0003857),
    preferring short/medium straight-chain acyl-CoA, e.g. 3-hydroxybutyryl-CoA
    PMID:9553139.
  4. Weak intrinsic 17-beta-hydroxysteroid / 3-alpha-hydroxysteroid / alcohol
    dehydrogenase     activity toward steroids, bile acids and 2-propanol
    PMID:10600649.
  5. Multiple steroid/bile-acid substrate specificities were characterized in vitro
    [PMID:12917011 "we here demonstrate novel activities of 17beta-HSD10. Both species variants oxidize the 20beta-OH and 21-OH groups in C21 steroids, and act as 7beta-OH dehydrogenases of ursodeoxycholic or isoursodeoxycholic acid"; "the human orthologue oxidizes the 7alpha-OH of chenodeoxycholic acid ... and cholic acid"].
  6. Oxidizes the 3-alpha-OH of allopregnanolone (brexanolone), a neurosteroid
    GABA-A modulator PMID:19706438.

  7. Also reported as a cardiolipin phospholipase C-like enzyme in vitro
    PMID:26338420.

  8. Structural, NON-catalytic moonlighting as MRPP2, an essential subunit of
    mitochondrial RNase P (with TRMT10C/MRPP1 and PRORP/MRPP3). This role is
    independent of the dehydrogenase activity.

  9. mt-RNase P is a protein-only enzyme that removes tRNA 5' extensions
    PMID:18984158.
  10. The MRPP1-MRPP2 (TRMT10C-SDR5C1) subcomplex is a bifunctional
    m1A9/m1G9 methyltransferase (SDR5C1/MRPP2 is the non-catalytic partner)
    PMID:23042678.
  11. The MRPP1/2 complex is a tRNA-maturation platform: after 5' cleavage it
    retains the tRNA and enhances ELAC2 3'-processing and presents the tRNA to the
    CCA-adding enzyme
    PMID:29040705.
  12. Confirmed by cryo-EM structures of mt-RNase P and mt-RNase Z (ELAC2/SDR5C1/TRMT10C)
    [PMID:38824131; PMID:39516281 "a SDR5C1 ... tetramer of SDR5C1 interacts with a monomer of TRMT10C that wraps around the mt pre-tRNA"].
  13. Binds tRNA [GOA: GO:0000049 tRNA binding IDA PMID:29040705].
  14. Localizes to mitochondrial matrix / nucleoid, initiating RNA processing there
    PMID:24703694.

Disease (HSD10 mitochondrial disease / MHBD deficiency)

X-linked, progressive neurodegeneration, psychomotor regression, seizures,
cardiomyopathy. Crucially, symptom severity does NOT correlate with residual
dehydrogenase activity — the pathogenic mechanism is loss of the non-enzymatic
mitochondrial (RNase P/tRNA processing, mitochondrial integrity) function
PMID:20077426;
[PMID:25575635 title "Mitochondrial energy failure in HSD10 disease is due to defective mtDNA transcript processing"];
PMID:24549042.
Pathogenic missense mutations (e.g. R130C, D86G, Q165H, K212E, P210S, R226Q, N247S,
V12L, V176M, E249Q) impair dehydrogenase AND tRNA methylation/processing
PMID:25925575;
PMID:26950678;
PMID:28888424.

ABAD/ERAB (Alzheimer / Aβ) — treat as disease-association binding, non-core

Historically discovered as an intracellular Aβ-binding protein (ERAB/ABAD) that
mediates neurotoxicity; identical to SCHAD
PMID:9553139.
The Aβ (APP) interaction is real but is a disease-association / binding role, not the
protein's evolved core function. Kept as non-core.

Localization

Authoritative: mitochondrion / mitochondrial matrix / mitochondrial nucleoid
[file UniProt: "SUBCELLULAR LOCATION: Mitochondrion ... Mitochondrion matrix, mitochondrion nucleoid"].
Older PINC (ProtInc) TAS annotations to cytoplasm and plasma membrane (both
from PMID:9338779, the 1997 ERAB discovery paper that mislabeled it as ER/plasma
membrane) are legacy mislocalizations superseded by all later work; marked
over-annotated (kept, not removed, per experimental-annotation policy, though these
are TAS not EXP).

Core functions authored

  1. MHBD / isoleucine catabolism (metabolic core): MF GO:0047015
    (3-hydroxy-2-methylbutyryl-CoA dehydrogenase activity) [+ broad GO:0003857
    3-hydroxyacyl-CoA dehydrogenase], BP GO:0006550 (L-isoleucine catabolic process),
    NAD binding GO:0051287, location GO:0005759 (mitochondrial matrix).
  2. mt-RNase P / tRNA 5'-processing (structural moonlighting core): MF GO:0000049
    (tRNA binding — subunit-level activity), BP GO:0097745 (mitochondrial tRNA 5'-end
    processing), in_complex GO:0030678 (mitochondrial ribonuclease P complex).

Action tally rationale