HADHB Review Notes

2026-02-05: Initial Review

Context

HADHB was identified during analysis of human Recon3D metabolic model as having a gene-reaction misassignment error. This prompted a full GO annotation review.

Recon3D Model Error

Finding: HADHB (Entrez ID 3034) is incorrectly assigned to histidase reaction (HISDr, EC 4.3.1.3) in Recon3D instead of fatty acid beta-oxidation thiolase reactions.

Source Reaction EC Subsystem
Recon3D HISDr (Histidase) 4.3.1.3 Histidine metabolism
Correct ACACT, KAT (Thiolases) 2.3.1.155, 2.3.1.16 Fatty acid oxidation

Impact: The correct thiolase reactions exist in Recon3D with GPRs containing 3030 (HADH), 3032 (HADH), 10449 (ACAA2) but are missing 3034 (HADHB). This means:
1. HADHB knockout simulations would incorrectly predict no effect on fatty acid oxidation
2. Histidine metabolism simulations would incorrectly include HADHB

Root cause: Likely a gene ID mapping error during model construction.

GO Annotation Errors Found

Two TAS annotations from 2003 (PMID:1550553) incorrectly assign HADHA activities to HADHB:

GO Term Activity Correct Gene
GO:0003857 3-hydroxyacyl-CoA dehydrogenase HADHA (alpha)
GO:0004300 enoyl-CoA hydratase HADHA (alpha)

Reason: PMID:1550553 (1992) characterized the whole MTP complex before subunit-specific activities were known. PMID:8135828 (1994) later showed:
- Alpha subunit (HADHA): hydratase + dehydrogenase activities
- Beta subunit (HADHB): thiolase activity ONLY

Key Literature

  1. PMID:1550553 (Carpenter 1992) - First purification of MTP from human liver, identified as trifunctional
  2. PMID:8135828 (Kamijo 1994) - Cloned both subunits, showed subunit-specific activities via expression
  3. PMID:29915090 (Liang 2018) - Cryo-EM structure of MTP at 4.2Å
  4. PMID:30850536 (Xia 2019) - Crystal structure at 3.6Å, detailed active site analysis

Disease Association

Mutations in HADHB cause Mitochondrial Trifunctional Protein Deficiency Type 2 (MTPD2) [MIM:620300]:
- Autosomal recessive
- Phenotype ranges from fatal early-onset cardiomyopathy to late-onset myopathy with peripheral neuropathy
- Loss of all three MTP activities due to complex destabilization

Alzheimer's Disease Relevance

HADHB is relevant to AD metabolic dysfunction through:
1. Mitochondrial fatty acid oxidation - Major energy source, impaired in AD
2. Ketone body production - Thiolase produces acetyl-CoA for ketogenesis
3. Lipid metabolism - Dysregulated in AD brains

The Recon3D error could affect metabolic modeling of AD brain metabolism.