BAAT

BAAT is the principal hepatic enzyme that catalyzes the final step of bile acid synthesis, conjugating bile acids to glycine or taurine; loss of BAAT activity in humans homozygous for a BAAT mutation leaves only unconjugated bile acids in serum, establishing that the enzyme is required for bile acid amino acid conjugation in vivo (PMID:12704386). Baat knockout mice confirm this enzymatic role, producing a bile acid pool dominated by unconjugated cholic acid, although residual host-derived glycine-conjugated and microbially conjugated bile acids persist, indicating BAAT is the primary but not the sole route of conjugation in mice (PMID:36243101). Through its control of conjugated bile acid production, BAAT supports early post-natal lipid and fat-soluble vitamin absorption — its loss in mice causes post-natal growth deficits, reduced fat pad and liver mass, reduced hepatic glycogen and vitamin A stores, and increased phospholipid excretion (PMID:36243101) — and shapes the composition of the early-life gut microbiome (PMID:36243101). In humans, BAAT genotype modifies the penetrance of familial hypercholanemia in an oligogenic interaction with TJP2 mutations (PMID:12704386).

1. 2003 High

   Established that BAAT is genetically and enzymatically required for bile acid amino acid conjugation in humans, resolving whether the conjugation step depends on this enzyme in vivo.

   Evidence Human genetic analysis of Amish familial hypercholanemia patients with functional enzyme assay and serum bile acid profiling showing only unconjugated bile acids in homozygous carriers

   PMID:12704386

   Open questions at the time

   • Does not resolve the structural or kinetic basis of glycine vs. taurine selectivity
   • Subcellular site of conjugation not dissected in this study
2. 2003 Medium

   Placed BAAT within an oligogenic disease framework by showing its genotype modifies penetrance of familial hypercholanemia in TJP2-mutant individuals, linking conjugation to enterohepatic transport phenotypes.

   Evidence Genetic epistasis analysis in Amish FHC pedigrees comparing single TJP2 versus double TJP2/BAAT mutation carriers

   PMID:12704386

   Open questions at the time

   • Oligogenic model not independently replicated outside this population
   • Molecular mechanism connecting BAAT loss to altered TJP2-driven transport not defined
3. 2022 High

   Defined BAAT as the primary but non-exclusive route of bile acid conjugation, showing residual host and microbial conjugation persists in its absence.

   Evidence Baat-/- mouse with LC-MS bile acid profiling of liver and feces plus antibiotic treatment to separate microbial from host conjugation

   PMID:36243101

   Open questions at the time

   • Identity of the residual host conjugating enzymes (e.g. Acnat1/2) inferred but not directly demonstrated
   • Human relevance of mouse-specific peroxisomal duplications unaddressed
4. 2022 Medium

   Connected BAAT-dependent conjugation to whole-organism physiology, establishing its importance for early post-natal lipid and fat-soluble vitamin absorption and growth.

   Evidence Baat-/- mouse phenotyping: body weight, tissue mass, glycogen histology, and fat-soluble vitamin store measurements at three weeks

   PMID:36243101

   Open questions at the time

   • Cellular mechanism linking conjugation loss to each phenotype not directly dissected
   • Whether catch-up growth fully normalizes downstream metabolism unknown
5. 2022 Medium

   Extended BAAT function beyond the host by showing its conjugation activity shapes early-life intestinal microbial community composition.

   Evidence 16S rRNA gut microbiome profiling of Baat-/- mice at multiple developmental time points

   PMID:36243101

   Open questions at the time

   • Mechanism linking specific bile acid species to particular microbial shifts not dissected
   • Single method (16S sequencing) without functional microbiome validation

• The structural basis of BAAT substrate selectivity (glycine vs. taurine), its subcellular conjugation site, and the human-specific consequences distinguishing it from mouse-specific paralogs remain unresolved.
• No structural or kinetic mechanism for amino acid donor selectivity in the corpus
• Human enzymes accounting for any residual conjugation not identified