CYP11B1 (P15538) review notes

Gene identity

Human steroid 11-beta-hydroxylase, cytochrome P450c11 / P-450(11)beta / CYPXIB1.
Mitochondrial inner-membrane cytochrome P450 (heme-thiolate), 503 aa, N-terminal
mitochondrial transit peptide (residues 1-24), heme axial Cys ligand at position 450.
EC 1.14.15.4. HGNC:2591, gene on chromosome 8q22 adjacent to paralog CYP11B2.

Catalyses the FINAL step of cortisol (glucocorticoid) synthesis: 11beta-hydroxylation of
11-deoxycortisol -> cortisol, and 11-deoxycorticosterone (21-hydroxyprogesterone) ->
corticosterone. [file:human/CYP11B1/CYP11B1-uniprot.txt "11beta position, yielding cortisol or corticosterone, respectively"]
Uses the mitochondrial adrenodoxin electron-transfer system: NADPH -> FDXR
(adrenodoxin/ferredoxin reductase, FAD) -> FDX1/FDX2 ([2Fe-2S] adrenodoxin/ferredoxin)
-> CYP11B1. [PMID:18215163 abstract; UniProt FUNCTION]
Reaction (RHEA:46100): 11-deoxycortisol + 2 reduced [adrenodoxin] + O2 + 2 H+ =
cortisol + 2 oxidized [adrenodoxin] + H2O.
Km ~338 uM for 11-deoxycortisol, ~180 uM for 21-hydroxyprogesterone; kcat 1.67 / 0.85 s-1
(recombinant enzyme, PMID:18215163).
Also 11beta-hydroxylates adrenal androgens (androstenedione -> 11OH-androstenedione;
testosterone -> 11beta,17beta-diOH-androstenedione) — secondary androgen-pathway role.

CYP11B1 and CYP11B2 are >93% identical at the protein level. [PMID:15026188 "their primary structure is 93% identical"; PMID:2256920 "93% identical"]
CYP11B1 is the GLUCOCORTICOID-branch enzyme; CYP11B2 is the MINERALOCORTICOID/aldosterone-branch enzyme.
CYP11B1 has only weak 18-hydroxylase and NO 18-oxidase activity, so it CANNOT make aldosterone.
[file quote "Due to its lack of 18-oxidation activity, it is incapable of generating" aldosterone;
PMID:2256920 "P-450(11)beta substantially fails to catalyze the reaction to form aldosterone"]
Consequence for review: "aldosterone biosynthetic process" annotations on CYP11B1 are
over-annotations (belongs to CYP11B2 / bovine CYP11B1 which is bifunctional). The IBA MF
term "corticosterone 18-monooxygenase activity" reflects a weak residual activity; keep
non-core.

Mitochondrion inner membrane, peripheral membrane protein. [file "Mitochondrion inner membrane"]
HTP mitochondrial proteome (PMID:34800366) supports mitochondrial localization.
IC (PMID:8506298) and TAS (PMID:15026188, Reactome) support inner-membrane.

Expressed in zona fasciculata/reticularis of the adrenal cortex.
[file "Expressed in the zona fasciculata/reticularis of"]
ACTH (peptide hormone) is the primary trophic/transcriptional stimulus -> supports
"cellular response to peptide hormone stimulus".
NRSF/NRSE regulates CYP11B1 and CYP11B2 transcription; K+ and angiotensin II augment
transcription (PMID:19342457, H295R adrenocortical cells). K+ response is more central
to CYP11B2/aldosterone; keep CYP11B1 K+ annotation non-core.

11beta-hydroxylase deficiency congenital adrenal hyperplasia = Adrenal hyperplasia 4
(AH4, MIM:202010); second commonest form of CAH; hypertensive form from
11-deoxycorticosterone (DOC) excess plus androgen excess/virilization.
PMID:8506298
Common CAH mutations cluster in exons 6-8 (e.g. R448H). [PMID:8506298; PMID:2022736]
Hyperaldosteronism familial type 1 (HALD1, glucocorticoid-remediable) arises from a
CYP11B1/CYP11B2 chimeric gene (ACTH-driven CYP11B1 promoter + CYP11B2 coding).

Core MF: GO:0004507 steroid 11-beta-monooxygenase activity (ACCEPT).
Core BP: GO:0034651 cortisol biosynthetic process + GO:0006704 glucocorticoid biosynthetic
process (ACCEPT).
Core CC: GO:0005743 mitochondrial inner membrane (ACCEPT).
Cofactor: GO:0020037 heme binding + GO:0005506 iron ion binding (ACCEPT).
Over-annotations: GO:0032342 aldosterone biosynthetic process (belongs to CYP11B2),
GO:0008203 cholesterol metabolic process (CYP11A1 role, IBA over-propagation),
GO:0006955 immune response (downstream glucocorticoid effect).
Non-core physiology/regulation: blood pressure, glucose homeostasis, K+/hormone responses,
peptide hormone response, sterol/cortisol metabolic (parent), mitochondrion (broad).