Carbonic anhydrase II (CA2) is a zinc metalloenzyme widely present in vertebrate tissues, mainly distributed in red blood cells, kidneys, gastric mucosa and the central nervous system. As the most active isoenzyme in the carbonic anhydrase family, it plays a core role in maintaining physiological processes such as acid-base balance, electrolyte secretion and gas exchange in the body by reversibly catalyzing the conversion of carbon dioxide and water into bicarbonate and protons. This enzyme was first discovered by the British scientist David Keilin in 1932. Its high-resolution crystal structure was resolved in the 1970s and became a classic model in enzymological research. The highly efficient catalytic property of CA2 (capable of converting millions of substrate molecules per second) makes it an ideal object for studying the catalytic mechanism of enzymes and the functions of metalloproteins. The related achievements have greatly promoted the development of bioinorganic chemistry and physiology. The clinical application of its inhibitor acetazolamide has initiated a new paradigm for drug design targeting enzymes.
CA2 is a zinc metalloenzyme with a molecular weight of approximately 29 kDa. Its precise molecular weight may vary slightly due to minor differences in amino acid sequences among species.
| Species | Human | Mice | Cows | Rats | Chickens |
| Molecular Weight (kDa) | 29.0 | 28.9 | 29.1 | 28.8 | 29.2 |
| Primary Structural Differences | Highly conserved active sites | Highly homologous to human CA2 (~80%) | Catalytic efficiency is slightly lower | Different tissue distributions | High thermal stability |
CA2 is composed of approximately 260 amino acids, forming a typical β -folded barrel structure (TIM barrel). Its active center contains a zinc ion (Zn²⁺), which is coordinated by three histidine residues (His94, His96, His119) and a water molecule. This structure enables CA2 to reversibly catalyze the CO₂ hydration reaction at an extremely high catalytic rate (converting 10⁶ CO₂ molecules per second).
Fig. 1 Schematic diagram of the pH regulation mechanism of the tumor microenvironment mediated by CA2.1
Key structural properties of CA2:
CA2 is the core functions of catalytic carbon dioxide (CO₂) reversible hydration reaction, but it also plays a key role in many physiological processes, including acid-base balance adjustment, ion transport and cellular metabolism, etc.
| Function | Description |
| CO₂ hydration catalysis | Efficient catalytic CO₂ + H₂O = HCO₃⁻+ H⁺, maintain intracellular and external pH balance, support respiration and metabolic processes. |
| Acid-base balance adjustment | Regulation of HCO₃⁻ concentration stabilizes pH in blood and tissues and prevents acidosis or alkalosis. |
| Electrolyte secretion | Participation in kidney and gastric mucosa HCO₃⁻ and H⁺ transhipment, affect the urine acidification and gastric acid secretion. |
| Bone resorption and calcification | Provide acidic microenvironments in osteoclasts, promote bone matrix dissolution, and participate in bone calcification process. |
| Cerebrospinal fluid generation | Regulating the concentration of HCO₃⁻ in the choroid plexus affects the secretion of cerebrospinal fluid and the stability of intracranial pressure. |
| Regulation of the tumor microenvironment | In the high expression of cancer cells by acidification environment promote the tumor invasion and metastasis. |
The catalytic efficiency of CA2 is one of the most efficient enzymes known, and its activity is regulated by pH and the binding state of zinc ions.
1. Insausti, Ricardo, Monica Muñoz‐López, and Ana Maria Insausti. "The CA2 hippocampal subfield in humans: A review." Hippocampus 33.6 (2023): 712-729. https://doi.org/10.1002/hipo.23547
This study shows that although the CA2 region of the hippocampus is tiny (about 500 micrometers wide in humans), it plays a key role in social memory and anxiety. Its longitudinal extension is approximately 30 millimeters and is closely related to the pathological mechanisms of Alzheimer's disease, schizophrenia and temporal lobe epilepsy.
2. Tzakis, Nikolaos, and Matthew R. Holahan. "Social memory and the role of the hippocampal CA2 region." Frontiers in behavioral neuroscience 13 (2019): 233. https://doi.org/10.3389/fnbeh.2019.00233
This study indicates that the CA2 region of the hippocampus was once thought to be an extension of CA3, but the latest research reveals that it has unique neural connections and functions, which are particularly crucial for social recognition and memory. Its dysfunction may be related to social disorders.
3. Zhao, Kai, et al. "Inhibition of carbonic anhydrase 2 overcomes temozolomide resistance in glioblastoma cells." International Journal of Molecular Sciences 23.1 (2021): 157. https://doi.org/10.3390/ijms23010157
Studies have shown that carbonic andiase CA2 plays a key role in the recurrence of glioblastoma and temozolomide resistance. The combined use of temozolomide and the CA2 inhibitor bromoetholomide can effectively overcome drug resistance by inducing autophagy.
4. Haapasalo, Joonas, et al. "The expression of carbonic anhydrases II, IX and XII in brain tumors." Cancers 12.7 (2020): 1723. https://doi.org/10.3390/cancers12071723
This article indicates that carbonic anhydride enzyme (CAs), as a key metallic enzyme regulating pH balance, is abnormally expressed in various brain tumors such as glioma, medulloblastoma, and meningioma. Among them, CA II, CA IX, and CA XII are significantly associated with tumorigenesis, progression, and poor prognosis. Inhibitors targeting these subtypes have shown the potential to reverse the acidic microenvironment of tumors and enhance the efficacy of existing therapies, providing a new direction for improving the prognosis of patients with brain tumors.
5. Alexander, Georgia M., et al. "Social and novel contexts modify hippocampal CA2 representations of space." Nature communications 7.1 (2016): 10300. https://doi.org/10.1038/ncomms10300
This study indicates that the hippocampal CA2 region encodes social information (such as new/familiar peers) and novel object information through a unique "global remapping" mechanism (altering the spatial coding pattern of positional cells without affecting the neuronal discharge frequency or i.e., early gene expression), while the CA1 region does not have this characteristic. This reveals that the CA2 region may achieve the specific storage of social and episodic memory by reconstructing existing spatial representations.
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