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CYP11B2

Official Full Name
cytochrome P450 family 11 subfamily B member 2
Organism
Homo sapiens
GeneID
1585
Background
This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the mitochondrial inner membrane. The enzyme has steroid 18-hydroxylase activity to synthesize aldosterone and 18-oxocortisol as well as steroid 11 beta-hydroxylase activity. Mutations in this gene cause corticosterone methyl oxidase deficiency. [provided by RefSeq, Jul 2008]
Synonyms
CPN2; ALDOS; CYP11B; CYP11BL; CYPXIB2; P450C18; P-450C18; P450aldo;
Bio Chemical Class
Paired donor oxygen oxidoreductase
Protein Sequence
MALRAKAEVCVAAPWLSLQRARALGTRAARAPRTVLPFEAMPQHPGNRWLRLLQIWREQGYEHLHLEMHQTFQELGPIFRYNLGGPRMVCVMLPEDVEKLQQVDSLHPCRMILEPWVAYRQHRGHKCGVFLLNGPEWRFNRLRLNPDVLSPKAVQRFLPMVDAVARDFSQALKKKVLQNARGSLTLDVQPSIFHYTIEASNLALFGERLGLVGHSPSSASLNFLHALEVMFKSTVQLMFMPRSLSRWISPKVWKEHFEAWDCIFQYGDNCIQKIYQELAFNRPQHYTGIVAELLLKAELSLEAIKANSMELTAGSVDTTAFPLLMTLFELARNPDVQQILRQESLAAAASISEHPQKATTELPLLRAALKETLRLYPVGLFLERVVSSDLVLQNYHIPAGTLVQVFLYSLGRNAALFPRPERYNPQRWLDIRGSGRNFHHVPFGFGMRQCLGRRLAEAEMLLLLHHVLKHFLVETLTQEDIKMVYSFILRPGTSPLLTFRAIN
Open
Disease
Hypertension
Approved Drug
0
Clinical Trial Drug
2 +
Discontinued Drug
0

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Detailed Information

The CYP11B2 gene makes an enzyme that is part of the cytochrome P450 family of proteins. These enzymes handle lipids, break down medicines, and synthesize steroids among other biological functions. Usually functioning as monooxygenases, cytochrome P450 enzymes may also perform other redox reactions. Mostly, CYP11B2 supports synthesis aldosterone, a kind of mineral hormone. Various hormone-related problems may result from flaws in its functioning.

Function and Structure of CYP11B2

The protein made by the CYP11B2 gene mainly helps produce aldosterone. Aldosterone is the main mineralocorticoid hormone in the body, responsible for managing blood pressure, keeping water and salt balance, and controlling blood potassium levels. The enzyme makes aldosterone in a part of the adrenal cortex called the zona glomerulosa. CYP11B2 helps convert 11-deoxycorticosterone into aldosterone through three main steps: first, it adds a hydroxyl group (11-β hydroxylation), and then it makes two changes at carbon 18 (C18 oxidations). This step is the last part of making aldosterone.

In addition to aldosterone, CYP11B2 also makes 18-hydroxycorticosterone and 18-oxocortisol, which are usually found in small amounts in healthy people. In some health problems, particularly in people with primary aldosteronism (PA), the amounts of 18-hydroxycorticosterone and 18-oxocortisol increase a lot. CYP11B2 plays a key role in steroid metabolism and control by producing these molecules.

CYP11B2 is part of the cytochrome P450 family and has common features like an iron-containing heme group. CYP11B2 binds to oxygen and adds one oxygen atom to the target while turning the other oxygen atom into water. This process needs NADPH and helper proteins like electron transport proteins FDXR and ferredoxins FDX1 or FDX2.

Relationship of CYP11B2 with Diseases

Mutations or abnormal expression of the CYP11B2 gene are closely associated with various endocrine disorders, particularly those related to aldosterone synthesis. Particularly those connected to aldosterone production, mutations or aberrant expression of the CYP11B2 gene are strongly linked to certain endocrine diseases. Primary aldosteronism and a deficiency of an enzyme called corticosterone methyl oxidase are the most often occurring disorders. Primary aldosteronism results from excessively much aldosterone production by the adrenal glands. This causes the body to retain more sodium, lose too much potassium, elevate blood pressure, and could result in metabolic alkalosis. This disorder may result from changes or defects in the CYP11B2 gene.

Secondary high blood pressure most often results from primary aldosteronism (PA). Usually, it results from either bilateral adrenal hyperplasia—enlargement of both glands—or an adrenal adenoma, a tumor on one gland. This disorder causes aldosterone to be produced unregulated, independent of blood volume or salt levels. Long-term high aldosterone levels may elevate blood pressure, promote potassium loss, and lead to a disorder known as metabolic alkalosis. Linked to cardiac disorders, this may make blood pressure regulation more difficult. According to several studies, persons with PA have a much higher risk of cardiac diseases like stroke, heart attack, and irregular heartbeat than those with normal high blood pressure.

Changes in the CYP11B2 gene induce corticosterone methyl oxidase deficiency. This creates several hormone-related disorders and influences the balance of water and salt in the body by affecting aldosterone and other hormones. Clinical signs of corticosterone methyl oxidase insufficiency could include metabolic acidosis, hypokalemia, and hypotension.

Genetic and Phenotypic Diversity of CYP11B2

CYP11B2 mutations are involved in primary aldosteronism and some inherited hypertension conditions. Genetic hypertension often involves changes in genes that can affect how the body makes aldosterone, leading to irregular control of aldosterone levels.

Familial Hyperaldosteronism (FH) is a genetic condition strongly linked with CYP11B2 variants. FH has several forms, and the most common one is FH type I. This type of hyperaldosteronism is caused by the gene fusion of CYP11B2 and CYP11B1, leading to unchecked production of aldosterone synthase throughout the adrenal cortex, resulting in abnormally high aldosterone release levels.

Besides FH Type I, FH Type II and FH Type III are subtypes of familial hyperaldosteronism. FH Type II involves other mutations or phenotypic alterations of CYP11B2, while FH Type III is associated with novel genetic variations, such as ion channel gene mutations. These genetic forms are generally passed through dominant inheritance patterns, causing early-onset or severe hypertension and electrolyte imbalances.

Figure 1: Familial hyperaldosteronism (FH) involves distinct genetic mutations affecting aldosterone production, with FH-I caused by CYP11B1/CYP11B2 fusion, FH-II by CLCN2 gene mutations, FH-III by KCNJ5 mutations, and FH-IV by CACNA1H mutations, with targeted treatments developed mainly for FH-I using glucocorticoids and potential pharmacological options for others in development.Figure 1. Familial hyperaldosteronism variants involve distinct genetic mutations affecting aldosterone production, with targeted treatments mainly available for FH-I. (Zennaro MC, et al., 2020)

Clinical Manifestations and Diagnosis of Primary Aldosteronism

Clinical symptoms of primary aldosteronism usually include hypertension, hypokalemia, and metabolic alkalosis. Abnormal aldosterone production causes patients to hold on to water and salt while losing too much potassium. This can lead to high blood pressure and low potassium symptoms.

To diagnose primary aldosteronism, doctors look for a high ratio of aldosterone to renin in the blood. Common diagnostic tests include oral sodium loading tests, saline drip tests, and fludrocortisone suppression tests. After confirmation, more tests like CT scans and adrenal venous sampling (AVS) are needed to determine if the condition is single (which can be treated by removing the tumor through surgery) or bilateral hyperplasia (which needs medical treatment).

Prospects and Challenges of Targeted Therapy

With in-depth research on the CYP11B2 gene and its functions, prospects for targeted therapy are emerging.  The main methods include using medications to block the production or effects of aldosterone. For example, drugs that block mineralocorticoid receptors, like spironolactone, are commonly used to treat primary aldosteronism. Adrenalectomy is the usual treatment for primary aldosteronism (PA) caused by a single tumor, while medication is the main option for people with paired adrenal hyperplasia.

Research into novel targeted drugs is underway, particularly for conditions involving CYP11B2 mutations or overexpression. Regulating CYP11B2 expression or inhibiting excessive aldosterone synthesis through drugs can effectively mitigate symptoms caused by excessive aldosterone. Furthermore, gene editing technologies like CRISPR/Cas9 present new possibilities for gene therapy, with future gene correction strategies potentially applying to related disease treatments.

References:

  1. Gomez-Sanchez CE, Kuppusamy M, et al. Disordered CYP11B2 Expression in Primary Aldosteronism. Horm Metab Res. 2017 Dec;49(12):957-962.
  2. Davies E, Kenyon CJ. CYP11B2 polymorphisms and cardiovascular risk factors. J Hypertens. 2003 Jul;21(7):1249-53.
  3. Zennaro MC, Boulkroun S, et al. Pathogenesis and treatment of primary aldosteronism. Nat Rev Endocrinol. 2020 Oct;16(10):578-589.
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