CA1 (gene)

Structure

The human CA1 protein contains an N-terminus active site, zinc binding site, and substrate-binding site. The crystal structure of the human CA1-bicarbonate anion complex reveals the geometry of two H-bonds between the Glu106-Thr199 pair and the Glu117-His119 pair, and one pi H-bond between a water molecule and the phenyl ring of the Tyr114 residue. The product inhibition of CA1 via bicarbonate anions is correlated to the proton localization change on His119. So the Glu117-His119 H-bond is considered to regulate the ionicity of the zinc ion and the binding strength of the bicarbonate anion.

Mechanism

The reaction catalyzed by CA1 is the same as other carbonic anhydrase family proteins:

:CO2 + H2O -[\ce{Carbonic~anhydrase}] H2CO3

(in tissues - high CO2 concentration)

The CA1-catalyzed reaction has a relatively low reaction affinity (Km) of 4.0 mM for CO2, turnover number (Kcat) of , and catalytic efficiency (Kcat/Km) of comparing to other isozymes of the α-CA family of carbonic anhydrases. The turnover rate and catalytic rate of CA1 are only about 10% that of CA2 (Kcat: , Kcat/Km: ).

Function

Carbonic anhydrase 1 belongs to α-CA sub-family and is localized in the cytosol of red blood cell, GI tract, cardiac tissues and other organs or tissues. Transmembrane transport of CA-produced bicarbonate contributes significantly to cellular pH regulation.

In a human zinc-activated variant of CA1, the Michigan Variant, a single point mutation changes His 67 to Arg in a critical region of the active site. This variant of the zinc metalloenzyme appears to be unique in that it possesses esterase activity that is specifically enhanced by added free zinc ions.

Clinical significance

CA1 activation is associated with worsened pathological remodeling in human ischemic diabetic cardiomyopathy. In diabetic mellitus type 2 patients with postinfarct heart failure who were undergoing surgical coronary revascularization, myocardial levels of CA1 were sixfold higher than nondiabetic patients. Elevated CA1 expression was mainly localized in the cardiac interstitium and endothelial cells. Furthermore, high glucose-induced elevation of CA1 hampers endothelial cell permeability and determines endothelial cell apoptosis in vitro.

CA1 also mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation and serine protease factor XIIa generation. These phenomena induce proliferative diabetic retinopathy and diabetic macular edema disease progression, which represent leading causes of vision loss.

As CA1 is an important therapeutic target, development of its inhibitors will contribute to disease treatment. Compared to other CA family members, CA1 has relatively low affinity to common CA inhibitors. Nonetheless, it has medium affinity for CA inhibitor sulfonamides.

Interactions

CA1 has been shown to interact with:

• TFCP2
• HSD17B7
• MAPK6

These interactions have been confirmed using the high throughput method (one hit)

References

References

1. "Expasy - ProtParam".
2. (Aug 1991). "Physical mapping of the human carbonic anhydrase gene cluster on chromosome 8". Genomics.
3. "Entrez Gene: CA1 carbonic anhydrase I".
4. "CA1 - Carbonic anhydrase 1 - Homo sapiens (Human) - CA1 gene & protein".
5. (Aug 1994). "Enzyme-substrate interactions. Structure of human carbonic anhydrase I complexed with bicarbonate". Journal of Molecular Biology.
6. Carbonic acid has a pK_a of around 6.36 (the exact value depends on the medium) so at pH 7 a small percentage of the bicarbonate is protonated. See [[carbonic acid]] for details concerning the equilibria HCO{{su
7. (Oct 1999). "Carbonic anhydrase catalyzes cyanamide hydration to urea: is it mimicking the physiological reaction?". Journal of Biological Inorganic Chemistry.
8. (2002-05-01). "The catalytic mechanism of carbonic anhydrase: implications of a rate-limiting protolysis of water". Accounts of Chemical Research.
9. (2013-01-01). "Quantification of carbonic anhydrase gene expression in ventricle of hypertrophic and failing human heart". BMC Cardiovascular Disorders.
10. (May 2002). "Crystal structure of a zinc-activated variant of human carbonic anhydrase I, CA I Michigan 1: evidence for a second zinc binding site involving arginine coordination". Biochemistry.
11. (2014-01-01). "Carbonic anhydrase activation is associated with worsened pathological remodeling in human ischemic diabetic cardiomyopathy". Journal of the American Heart Association.
12. (Feb 2007). "Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation". Nature Medicine.
13. (Feb 2008). "Carbonic anhydrases: novel therapeutic applications for inhibitors and activators". Nature Reviews. Drug Discovery.
14. (Nov 2014). "A proteome-scale map of the human interactome network". Cell.
15. (2011-01-01). "Toward an understanding of the protein interaction network of the human liver". Molecular Systems Biology.
16. (Sep 2011). "A directed protein interaction network for investigating intracellular signal transduction". Science Signaling.