MMAA (Q8IVH4) review notes

Summary of verified biology

MMAA = "Methylmalonic aciduria type A protein" = the human cblA protein. It is a
mitochondrial GTPase of the SIMIBI-class G3E GTPase family, ArgK/MeaB subfamily
(UniProt SIMILARITY; InterPro IPR005129 GTPase_ArgK; Pfam PF03308 MeaB; CDD cd03114
MMAA-like). It is NOT the methylmalonyl-CoA mutase (MMUT/MUT) and does NOT itself
isomerize methylmalonyl-CoA. Instead it is a G-protein chaperone / cofactor-maintenance
protein for MMUT.

Deep research: just deep-research recipe is absent in this worktree (no
-deep-research-*.md produced or fabricated). Grounded instead in the UniProt record,
the 6 cached primary publications, GOA, and ~/repos/dismech/kb/disorders/Methylmalonic_Acidemia.yaml.

Core functional facts (with provenance)

• GTPase / GTP binding. Crystallized GDP-bound (PDB 2WWW, res 72-418); binds and
  hydrolyzes GTP; GTPase activity is stimulated ~by MMUT (GAP effect).
  PMID:20876572
  [UniProt CATALYTIC ACTIVITY: "GTP + H2O = GDP + phosphate + H(+); Rhea:RHEA:19669"; ACTIVITY REGULATION "GTPase activity is stimulated by MMUT"]
  KM(GTP) 42 uM (PMID:28497574), kcat 0.201 min-1. GTP-binding loops at 150-158, 292, 328-330.

• Gatekeeper / AdoCbl delivery to MMUT (GTP-dependent). Gates the transfer of
  adenosylcobalamin (AdoCbl) from MMAB (ATR) onto MUT apoenzyme; complex formation is
  nucleotide-selective (GMPPNP over GDP) and requires MUT apoenzyme.
  PMID:20876572
  [PMID:28497574 "MMAA regulates the incorporation of the cofactor adenosylcobalamin (AdoCbl), generated from the MMAB adenosyltransferase, into the destination enzyme methylmalonyl-CoA mutase (MUT)"; "all mutations interfered with gating the transfer of AdoCbl from MMAB to MUT"]

• Protectase + reactivase (dual chaperone role toward MMUT). Protects MUT from
  progressive inactivation (slows formation of oxidized OH2Cbl / cob(II)alamin) and
  reactivates inactive MUT by GTP-hydrolysis-driven exchange of the damaged cofactor.
  PMID:21138732
  [PMID:28943303 "the complex formation of hMCM/hMMAA decreases the rate of oxidized cofactor formation, protecting the hMCM enzyme"; "hMMAA is able to remove the damaged cofactor through GTP hydrolysis"]

• Allosteric regulation of oligomerization. Human MCM-CblA(MMAA) forms interconverting
  nucleotide-sensitive oligomers (M2C1, M2C2, M3C3...); GTPase-driven resolution to the
  loading-ready M2C1 state is required to load MCM with AdoCbl. Switch III patient
  mutations corrupt this. [PMID:31056463 full text].

• Homodimer. [PMID:20876572 "MMAA ... α2 homodimer"; UniProt SUBUNIT "Homodimer";
  GO:0042802/GO:0042803 IDA].

• Localization. Mitochondrion (matrix; has cleaved mitochondrial transit peptide 1-65),
  colocalizes with MMUT; also detected cytoplasm/cytosol (IDA/HPA).
  PMID:28943303
  [UniProt SUBCELLULAR LOCATION: Mitochondrion; Cytoplasm; TRANSIT 1..65 Mitochondrion]

• Disease. Deficiency = methylmalonic aciduria, cblA type (MACA; MIM 251100), autosomal
  recessive, often vitamin-B12(hydroxocobalamin)-responsive. cblA mutations reduce the
  mitochondrial AdoCbl pool. [UniProt DISEASE; disorders KB Methylmalonic_Acidemia.yaml;
  PMID:31056463 "AdoCbl ... reduced to 3.3±1.6 % of the total pool in fibroblasts from cblA patients"]

Annotation-level notes

• MF GTPase activity (GO:0003924) IDA x3 (20876572, 28943303, 21138732), IMP (28497574),
  IBA, IEA — all ACCEPT; this is a core MF.
• MF GTP binding (GO:0005525) IDA x2, IEA — ACCEPT (component of the GTPase MF).
• MF molecular carrier activity (GO:0140104) TAS(Reactome R-HSA-3159259) + IDA(31056463,
  MGI). MMAA does not itself carry/bind cobalamin as its cargo — it is the G-protein that
  GATES AdoCbl transfer (AdoCbl is carried/handed off between MMAB and MUT). "Molecular
  carrier activity" is a defensible but imprecise/over-annotation of the gating role; the
  more precise MF is GTPase activity and the role is a regulatory/chaperone one. MODIFY /
  MARK_AS_OVER_ANNOTATED (not itself the cofactor carrier).
• BP cobalamin metabolic process (GO:0009235) IDA/TAS — ACCEPT (core BP: intracellular B12
  handling / AdoCbl delivery).
• protein binding (GO:0005515) IPI with MMUT (P22033) — bare "protein binding"; the real
  interactant is MMUT and captured better as the chaperone/complex-formation role.
  MARK_AS_OVER_ANNOTATED (do NOT REMOVE per policy).
• identical protein binding / protein homodimerization (GO:0042802/GO:0042803) IDA/IPI —
  ACCEPT (homodimer is real, structurally verified).
• CC mitochondrion (GO:0005739) IDA/IEA/HTP, mitochondrial matrix (GO:0005759) TAS x4 —
  ACCEPT. Mitochondrion IDA is core. Matrix (Reactome) is consistent.
• CC cytoplasm (GO:0005737) IBA/IEA/IDA and cytosol (GO:0005829) IDA(HPA) — MMAA is
  synthesized with a mito transit peptide and functions in the matrix; cytoplasm/cytosol
  signal likely reflects precursor / partial import / antibody localization. KEEP_AS_NON_CORE
  (real detection but not the core functional location).
• PMID:34800366 HTP mitochondrion — ACCEPT as corroborating (large-scale mito proteome).