CMA1

Official Full Name

chymase 1

Organism

Homo sapiens

GeneID

1215

Background

This gene encodes a chymotryptic serine proteinase that belongs to the peptidase family S1. It is expressed in mast cells and is thought to function in the degradation of the extracellular matrix, the regulation of submucosal gland secretion, and the generation of vasoactive peptides. In the heart and blood vessels, this protein, rather than angiotensin converting enzyme, is largely responsible for converting angiotensin I to the vasoactive peptide angiotensin II. Alternative splicing results in multiple variants. [provided by RefSeq, Apr 2015]

Synonyms

CYH; MCT1; chymase;

Bio Chemical Class

Peptidase

Protein Sequence

MLLLPLPLLLFLLCSRAEAGEIIGGTECKPHSRPYMAYLEIVTSNGPSKFCGGFLIRRNFVLTAAHCAGRSITVTLGAHNITEEEDTWQKLEVIKQFRHPKYNTSTLHHDIMLLKLKEKASLTLAVGTLPFPSQFNFVPPGRMCRVAGWGRTGVLKPGSDTLQEVKLRLMDPQACSHFRDFDHNLQLCVGNPRKTKSAFKGDSGGPLLCAGVAQGIVSYGRSDAKPPAVFTRISHYRPWINQILQAN

Open

Disease

Atopic eczema, Cardiovascular disease, Chronic obstructive pulmonary disease, Gram-positive bacterial infection, Heart failure, Left ventricular failure, Myocardial infarction

Approved Drug

Clinical Trial Drug

5 +

Discontinued Drug

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Detailed Information

The CMA1 gene encodes an enzyme called Chymase 1, which is a serine protease with cleavage functions, belonging to the S1 peptidase family. This enzyme is primarily synthesized and secreted in mast cells, which are crucial in immune responses. One of the main functions of the CMA1 protein is to degrade the extracellular matrix and participate in regulating the secretion of submucosal glands and the production of vasoactive peptides. These peptide substances are essential for regulating vasodilation and immune responses. Additionally, in the heart and blood vessels, CMA1 serves as an important enzyme that converts angiotensin I to angiotensin II, similar to the function of angiotensin-converting enzyme (ACE).

Function and Physiological Role of the CMA1 Gene

1. Degradation of the Extracellular Matrix: CMA1 plays a significant role in the degradation of the extracellular matrix. Comprising different proteins, glycosaminoglycans, and glycoproteins, the extracellular matrix supports cells and shapes their migration and development. CMA1 aids in tissue remodeling and healing by cutting and destroying these matrix elements. The breakdown of the extracellular matrix helps immune cells to rapidly access injured or infected locations during inflammatory and immunological reactions.

2. Generation of Vasoactive Peptides: In the renin-angiotensin system, the CMA1 protein changes angiotensin I into angiotensin II, therefore causing vasoconstriction. Powerful vasoconstrictor angiotensin II may control fluid balance and raise blood pressure. CMA1 is therefore essential in cardiovascular illnesses, particularly in disorders brought on by angiotensin-converting enzyme deficits.

3. Regulation of Submucosal Gland Secretion: Additionally under control of CMA1 is the release of submucosal glands, a process essential for the operation of the gastrointestinal and respiratory systems. In these tissues, CMA1 affects the secretory composition, therefore controlling local immunological and inflammatory reactions. For example, the activation of CMA1 might help mast cells release different mediators during allergic reactions, therefore strengthening local immune responses.

Variations and Diseases of the CMA1 Gene

Variations in the CMA1 gene may lead to various diseases, particularly in the immune system and allergic reactions. CMA1 is closely associated with diseases such as cutaneous mastocytosis (cutaneous eosinophilic mastocytosis) and urticaria. These diseases are often accompanied by abnormal activation of allergic and inflammatory responses, with CMA1, being one of the major enzymes secreted by mast cells, participating in regulating these pathological processes.

For instance, mastocytosis is a disease caused by the proliferation or abnormal function of mast cells, often accompanied by symptoms in the skin, digestive system, or respiratory system. Research indicates that CMA1 plays a significant role in this process by regulating the release of inflammatory factors, exacerbating these symptoms.

Molecular Mechanisms of the CMA1 Gene

The biological functions of CMA1 rely on its molecular mechanisms. As a serine protease, the activity of CMA1 depends on its synthesis, storage, and activation within mast cells. The synthesis of CMA1 occurs first in the endoplasmic reticulum and Golgi apparatus, where it is packaged into granules along with other secretory components, stored within the cell. Upon stimulation of mast cells, these granules fuse with the cell membrane, releasing CMA1 to exert its biological functions.

Figure 1 outlines the functions of chymase in kidney disease. Red scissors symbolize confirmed enzymatic activity in kidney disease, while grey scissors represent potential activities. Green arrows highlight chymase protective roles, and red arrows denote its functions that may aggravate the disease. Figure 1. Chymase functions in kidney disease: activities and impacts. (Vibhushan S, et al., 2020)

During the maturation of CMA1, the involvement of endosomes and lysosomes is crucial for the formation of its final activity. The precursor form of CMA1 is cleaved into its physiologically active enzyme via a sequence of intricate endogenous cleavage events. This mechanism includes the control of glycosaminoglycans (such as heptin) and proteoglycans (such as serglycin) and calls for certain enzymes like cathepsin C.

Associated with many signaling pathways, the CMA1 gene is most tightly linked to the renin-angiotensin system (RAS). With CMA1 as a major enzyme involved in the conversion of angiotensin I to angiotensin II, RAS is essential in controlling blood pressure and fluid balance. Moreover, CMA1 is linked to peptide hormone metabolism and pharmacodynamics; abnormalities in these pathways could cause a spectrum of disorders.

References:

Ferrario CM, Ahmad S, et al. Is chymase 1 a therapeutic target in cardiovascular disease? Expert Opin Ther Targets. 2023 Jul-Dec;27(8):645-656.
Yahiro E, Miura S, et al. Chymase inhibitors. Curr Pharm Des. 2013;19(17):3065-71.
Atiakshin D, Buchwalow I, et al. Mast cell chymase: morphofunctional characteristics. Histochem Cell Biol. 2019 Oct;152(4):253-269.
Vibhushan S, Bratti M, et al. Mast Cell Chymase and Kidney Disease. Int J Mol Sci. 2020;22(1):302.

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