ArticleProceedings of the National Academy of Sciences of the United States of America2011
Intramolecular proton shuttle supports not only catalytic but also noncatalytic function of carbonic anhydrase II.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 98 citations in OpenAlex.
- Sex and genotype specificities of microvasculature and muscle remodeling in sub-Saharan sickle cell trait and disease.Blood advances · 2025Article
- Discovery of a second citric acid cycle complex.Heliyon · 2023Review
- Development of Human Carbonic Anhydrase II Heterobifunctional Degraders.Journal of medicinal chemistry · 2023Article
- The effect of pre-exercise alkalosis on lactate/pH regulation and mitochondrial respiration following sprint-interval exercise in humans.Frontiers in physiology · 2023Article
- Carbonic Anhydrases II and IX in Non-ampullary Duodenal Adenomas and Adenocarcinoma.The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society · 2021Article
- The two-cell model of glucose metabolism: a hypothesis of schizophrenia.Molecular psychiatry · 2021Review
- Proton Transport in Cancer Cells: The Role of Carbonic Anhydrases.International journal of molecular sciences · 2021Review
- Rethinking the Citric Acid Cycle: Connecting Pyruvate Carboxylase and Citrate Synthase to the Flow of Energy and Material.International journal of molecular sciences · 2021Review
- Heteromeric Solute Carriers: Function, Structure, Pathology and Pharmacology.Advances in experimental medicine and biology · 2021Review
- Carbonic anhydrases enhance activity of endogenous Na-H exchangers and not the electrogenic Na/HCOThe Journal of physiology · 2020Article
- Review
- Monocarboxylate transporters in cancer.Molecular metabolism · 2020Review
- CAIX forms a transport metabolon with monocarboxylate transporters in human breast cancer cells.Oncogene · 2020Article
- Astrocytes and neurons communicate via a monocarboxylic acid shuttle.AIMS neuroscience · 2020Review
- Iron-Deficiency Anemia Results in Transcriptional and Metabolic Remodeling in the Heart Toward a Glycolytic Phenotype.Frontiers in cardiovascular medicine · 2020Article
- Carbonic anhydrase IX and acid transport in cancer.British journal of cancer · 2020Review
- pH and male fertility: making sense on pH homeodynamics throughout the male reproductive tract.Cellular and molecular life sciences : CMLS · 2019Review
- Catalytically inactive carbonic anhydrase-related proteins enhance transport of lactate by MCT1.FEBS open bio · 2019Article
- Membrane-anchored carbonic anhydrase IV interacts with monocarboxylate transporters via their chaperones CD147 and GP70.The Journal of biological chemistry · 2019Article
- Energy Dynamics in the Brain: Contributions of Astrocytes to Metabolism and pH Homeostasis.Frontiers in neuroscience · 2019Review
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Carbonic anhydrases (CAs) catalyze the reversible hydration of CO(2) to HCO(3)(-) and H(+). The rate-limiting step in this reaction is the shuttle of protons between the catalytic center of the enzyme and the bulk solution. In carbonic anhydrase II (CAII), the fastest and most wide-spread isoform, this H(+) shuttle is facilitated by the side chain of His64, whereas CA isoforms such as carbonic anhydrase III (CAIII), which lack such a shuttle, have only low catalytic activity in vitro. By using heterologous protein expression in Xenopus oocytes, we tested the role of this intramolecular H(+) shuttle on CA activity in an intact cell. The data revealed that CAIII, shown in vitro to have ∼1,000-fold reduced activity as compared with CAII, displays significant catalytic activity in the intact cell. Furthermore, we tested the hypothesis that the H(+) shuttle in CAII itself can facilitate transport activity of the monocarboxylate transporters 1 and 4 (MCT1/4) independent of catalytic activity. Our results show that His64 is essential for the enhancement of lactate transport via MCT1/4, because a mutation of this residue to alanine (CAII-H64A) abolishes the CAII-induced increase in MCT1/4 activity. However, injection of 4-methylimidazole, which acts as an exogenous H(+) donor/acceptor, can restore the ability of CAII-H64A to enhance transport activity of MCT1/4. These findings support the hypothesis that the H(+) shuttle in CAII not only facilitates CAII catalytic activity but also can enhance activity of acid-/base-transporting proteins such as MCT1/4 in a direct, noncatalytic manner, possibly by acting as an "H(+)-collecting antenna."
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