ArticleBiochemistry2015
Catalytic Mechanism of Mammalian Adenylyl Cyclase: A Computational Investigation.
Article in Biochemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
What it found
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Who cites it
15 citing papers in PubMed, 37 citations in OpenAlex.
- Cholesterol Derivatives Regulate Adenylyl Cyclase 7 Activity by Binding CARC and CRAC Motifs in the Cytosolic Subunits.ACS omega · 2025Article
- Article
- Translation regulation in response to stress.The FEBS journal · 2024Review
- Functional and structural insights into the multi-step activation and catalytic mechanism of bacterial ExoY nucleotidyl cyclase toxins bound to actin-profilin.PLoS pathogens · 2023Article
- Examination of Intracellular GPCR-Mediated Signaling with High Temporal Resolution.International journal of molecular sciences · 2022Article
- Bacterial Nucleotidyl Cyclases Activated by Calmodulin or Actin in Host Cells: Enzyme Specificities and Cytotoxicity Mechanisms Identified to Date.International journal of molecular sciences · 2022Review
- Article
- Allosteric Inhibition of Adenylyl Cyclase Type 5 by G-Protein: A Molecular Dynamics Study.Biomolecules · 2020Article
- Molecular basis for GTP recognition by light-activated guanylate cyclase RhGC.The FEBS journal · 2020Article
- Probing the Structural Dynamics of the Catalytic Domain of Human Soluble Guanylate Cyclase.Scientific reports · 2020Article
- Regulation of adenylyl cyclase 5 in striatal neurons confers the ability to detect coincident neuromodulatory signals.PLoS computational biology · 2019Article
- Rhodopsin-cyclases for photocontrol of cGMP/cAMP and 2.3 Å structure of the adenylyl cyclase domain.Nature communications · 2018Article
- A molecular dynamics study of adenylyl cyclase: The impact of ATP and G-protein binding.PloS one · 2018Article
- International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases.Pharmacological reviews · 2017Review
- Structure and Activation of Soluble Guanylyl Cyclase, the Nitric Oxide Sensor.Antioxidants & redox signaling · 2017Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Adenylyl cyclase (AC) catalyzes the synthesis of cyclic AMP, an important intracellular regulatory molecule, from ATP. We propose a catalytic mechanism for class III mammalian AC based on density functional theory calculations. We employ a model of the AC active site derived from a crystal structure of mammalian AC activated by Gα·GTP and forskolin at separate allosteric sites. We compared the calculated activation free energies for 13 possible reaction sequences involving proton transfer, nucleophilic attack, and elimination of pyrophosphate. The proposed most probable mechanism is initiated by deprotonation of 3'OH and water-mediated transfer of the 3'H to the γ-phosphate. Proton transfer is followed by changes in coordination of the two magnesium ion cofactors and changes in the conformation of ATP to enhance the role of 3'O as a nucleophile and to bring 3'O close to Pα. The subsequent phosphoryl transfer step is concerted and rate-limiting. Comparison of the enzyme-catalyzed and nonenzymatic reactions reveals that the active site residues lower the free energy barrier for both phosphoryl transfer and proton transfer and significantly shift the proton transfer equilibrium. Calculations for mutants K1065A and R1029A demonstrate that K1065 plays a significant role in shifting the proton transfer equilibrium, whereas R1029 is important for making the transition state of concerted phosphoryl transfer tight rather than loose.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.