{"doi":"10.3390/ijms26136401","title":"Updating the Mechanism of Bicarbonate (HCO3−) Activation of Soluble Adenylyl Cyclase (sAC)","abstract":"Soluble adenylyl cyclase (sAC) is molecularly and biochemically distinct from other mammalian nucleotidyl cyclases. It is uniquely regulated directly by bicarbonate (HCO3−) and calcium (Ca2+) ions and is responsive to physiologic fluctuations in levels of its substrate, adenosine triphosphate (ATP). Our initial in vitro biochemical studies suggested two mechanisms for HCO3−-dependent elevation of sAC activity: increasing catalytic rate and relieving inhibition observed in the presence of supraphysiological levels of substrate, ATP. Structural and mutational studies revealed that HCO3− increases catalytic rate via the disruption of a salt bridge that facilitates productive interactions with the substrate. Here, we demonstrate that the HCO3− stimulation observed under supraphysiological ATP concentrations is due to the mitigation of ATP-dependent acidification. Therefore, we conclude that the sole physiologically relevant mechanism of HCO3− regulation of sAC is through its pH-independent effect facilitating productive substrate binding to the catalytic site.","journal":"International Journal of Molecular Sciences","year":2025,"id":526171,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9548,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1401695,"name":"Hayden Belliveau","orcid":null,"position":1,"is_corresponding":false},{"id":295617,"name":"Clemens Steegborn","orcid":"0000-0002-0913-1467","position":2,"is_corresponding":false},{"id":246034,"name":"Jochen Buck","orcid":"0000-0002-3568-5869","position":3,"is_corresponding":false},{"id":246035,"name":"Lonny R. Levin","orcid":"0000-0002-5204-6356","position":4,"is_corresponding":false},{"id":814254,"name":"Jacob Ferreira","orcid":"0000-0003-2146-9732","position":0,"is_corresponding":true}],"reference_count":17,"raw_metadata":null,"created_at":"2026-07-19T02:50:25.860105Z","pmid":"40650178","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}