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bile acid biosynthesis, neutral pathway

General Background The biosynthesis of bile acids is a major route of : CHOLESTEROL catabolism. It converts the hydrophobic, insoluble : CHOLESTEROL molecule into soluble bile acids. Accumulation of excess cholesterol has been shown to be a risk factor for several diseases, notably atherosclerosis. Expression of the enzymes involved in bile acid biosynthesis is highly regulated by transcription factors to ensure their availability during changing metabolic conditions. Inherited mutations in some of these enzymes result in a variety of severe metabolic disorders. In the liver, the primary bile acids are conjugated with : GLY or : TAURINE before secretion into the bile. Further conversion into secondary bile acids such as : DEOXYCHOLATE, or : CPD-7235 occurs through the action of microbial enzymes in the gut (see MetaCyc pathway : 7ALPHADEHYDROX-PWY). Four pathways for bile acid biosynthesis have been described. The neutral (classic) pathway begins with hydroxylation at the 7alpha ring position of : CHOLESTEROL (EC 1.14.13.17). The acidic (alternate) pathway begins with 27-hydroxylation of the : CHOLESTEROL side chain (EC 1.14.13.15). The 24-hydroxylase (EC 1.14.13.98) and 25-hydroxylase (EC 1.14.99.38) pathways begin with these respective side chain hydroxylations. The three side chain hydroxylations are followed by 7alpha hydroxylation (via EC 1.14.13.99 or EC 1.14.13.100). Hydroxylation at the 7alpha position is a characteristic of bile acids. All but one of these reactions are catalyzed by enzymes of the cytochrome P450 family. The acidic, 24-hydroxylase and 25-hydroxylase pathways have only been partly illustrated in the literature (later reaction steps were omitted). It should also be noted that the exact order of reactions in all of the bile acid biosynthetic pathways remains unclear because many of the intermediates are substrates for more than one biosynthetic enzyme. In addition, the relative contributions of the different pathways may vary by species, age and physiological condition (in . The neutral pathway is considered the quantitatively most important pathway in humans. The acidic pathway leads mainly to : CPD-15189 and may be more important in rats. The 24- and 25-hydroxylase pathways are considered minor pathways. Reviewed extensively in . About This Pathway This pathway shows the neutral (classic) pathway for the biosynthesis of two possible bile acid conjugates of : CHOLATE and : CPD-15189. It is represented here essentially as shown in and as shown in part in and . The pathway is initiated by hydroxylation at the 7alpha position of the : CHOLESTEROL ring structure, followed by reactions that further modify the : CHOLESTEROL rings, oxidize and shorten the side chain, and conjugate the bile acid with an amino acid to increase solubility. Free : CHOLATE may result from regulated action of peroxisomal coenzyme A thioesterase 2 on : CPD-202, although the biological consequences of changes in the ratio of free and conjugated forms are not understood. More than 98% of bile acids excreted from the liver are conjugated (in ). Humans and rats produce both : GLYCOCHOLIC_ACID and : CPD-3743. Mice produce : CPD-3743 due to difference in substrate specificity of their conjugating enzyme ( and reviewed in ). The enzymes in the pathway are found in multiple subcellular locations including the endoplasmic reticulum, cytosol, mitochondrion and peroxisome (as indicated on the enzyme display pages). These enzymes also function in steroid metabolism, very long chain fatty acid metabolism and vitamin D biosynthesis. Reviewed in . Oxysterols produced during bile acid biosynthesis also function in cholesterol homeostasis (reviewed in . A branch point after the second reaction at : CPD-1087 leads to a similar biosynthesis of : CPD-15189 derivatives in most mammalian species. This branch lacks the : CPLX-7680 step (as illustrated in ). : CHOLATE differs from : CPD-15189 by the presence of a hydroxyl group at the 12alpha position. The relevant enzymes in the pathway shown here are also active on the corresponding dihydroxy substrates that lead to : CPD-15189 derivatives . Other bile acids (and their derivatives) such as : Muricholates, : CPD-10534 and : CPD-7284 are also produced by mouse, bear and pig, respectively (in ).

from BIOCYC source record: HUMAN_PWY-6061
Type: pathway
Taxonomic scope
:
organism-specific biosystem
Organism
:
Homo sapiens
BSID:
545316

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