ArticleThe Journal of biological chemistry2009
Mechanism of cyclizing NAD to cyclic ADP-ribose by ADP-ribosyl cyclase and CD38.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
42 citing papers in PubMed, 82 citations in OpenAlex.
- Emerging roles of SIRT6 and its modulators in kidney diseases.Cell death discovery · 2026Review
- The evolving landscape of enzymatic technologies for precision synthesis of antibody-drug conjugates.Antibody therapeutics · 2026Review
- Targeting prostate cancer with site-specific antibody-drug conjugates enabled by tandemly fused ADP-ribosyl cyclases.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2025Article
- Synthesis of site-specific Fab-drug conjugates using ADP-ribosyl cyclases.Protein science : a publication of the Protein Society · 2024Article
- CD38 promotes hematopoietic stem cell dormancy.PLoS biology · 2024Article
- Apigenin: a natural molecule at the intersection of sleep and aging.Frontiers in nutrition · 2024Review
- Enzymology of CaCells · 2023Review
- Pangenomic analysis reveals plant NADProceedings of the National Academy of Sciences of the United States of America · 2023Article
- Review
- Cyclic ADP ribose isomers: Production, chemical structures, and immune signaling.Science (New York, N.Y.) · 2022Article
- Conceptual Framework for SARS-CoV-2-Related Lymphopenia.Advanced biomedical research · 2022Review
- Small Molecule CD38 Inhibitors: Synthesis of 8-Amino-Molecules (Basel, Switzerland) · 2021Article
- Selective targeting of CD38 hydrolase and cyclase activity as an approach to immunostimulation.RSC advances · 2021Article
- Neurotransmitters responsible for purinergic motor neurotransmission and regulation of GI motility.Autonomic neuroscience : basic & clinical · 2021Article
- Daratumumab and Nanobody-Based Heavy Chain Antibodies Inhibit the ADPR Cyclase but not the NADCancers · 2020Article
- Extracellular metabolism of the enteric inhibitory neurotransmitter β-nicotinamide adenine dinucleotide (β-NAD) in the murine colon.The Journal of physiology · 2020Article
- Review
- NADFrontiers in physiology · 2020Review
- Resolving the topological enigma in CaThe Journal of biological chemistry · 2019Review
- Metabolic aspects of neuronal degeneration: From a NADNeuroscience research · 2019Review
Corrections and comments
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
Abstract
Mammalian CD38 and its Aplysia homolog, ADP-ribosyl cyclase (cyclase), are two prominent enzymes that catalyze the synthesis and hydrolysis of cyclic ADP-ribose (cADPR), a Ca(2+) messenger molecule responsible for regulating a wide range of cellular functions. Although both use NAD as a substrate, the cyclase produces cADPR, whereas CD38 produces mainly ADP-ribose (ADPR). To elucidate the catalytic differences and the mechanism of cyclizing NAD, the crystal structure of a stable complex of the cyclase with an NAD analog, ribosyl-2'F-2'deoxynicotinamide adenine dinucleotide (ribo-2'-F-NAD), was determined. The results show that the analog was a substrate of the cyclase and that during the reaction, the nicotinamide group was released and a stable intermediate was formed. The terminal ribosyl unit at one end of the intermediate formed a close linkage with the catalytic residue (Glu-179), whereas the adenine ring at the other end stacked closely with Phe-174, suggesting that the latter residue is likely to be responsible for folding the linear substrate so that the two ends can be cyclized. Mutating Phe-174 indeed reduced cADPR production but enhanced ADPR production, converting the cyclase to be more CD38-like. Changing the equivalent residue in CD38, Thr-221 to Phe, correspondingly enhanced cADPR production, and the double mutation, Thr-221 to Phe and Glu-146 to Ala, effectively converted CD38 to a cyclase. This study provides the first detailed evidence of the cyclization process and demonstrates the feasibility of engineering the reactivity of the enzymes by mutation, setting the stage for the development of tools to manipulate cADPR metabolism in vivo.
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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.