Enzymatic synthesis and characterizations of cyclic GDP-ribose. A procedure for distinguishing enzymes with ADP-ribosyl cyclase activity.

Graeff, Richard; Walseth, Timothy F.; Fryxell, Kathryn; Branton, W. D.; Lee, Hon Cheung

doi:10.1016/s0021-9258(18)43806-9

Cited by 232 publications

(32 citation statements)

References 22 publications

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“…In addition to sensitivity, PC6 also shows exquisite selectivity toward SARM1 versus CD38 and N. crassa NADase (Graeff et al, 1994). All three possess NADase activity as detected by εNAD (Fig.…”

Section: Resultsmentioning

confidence: 93%

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Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate

Huang

Cai

et al. 2021

eLife

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SARM1 regulates axonal degeneration through its NAD-metabolizing activity and is a drug target for neurodegenerative disorders. We designed and synthesized fluorescent conjugates of styryl derivative with pyridine to serve as substrates of SARM1, which exhibited large red-shifts after conversion. With the conjugates, SARM1 activation was visualized in live cells following elevation of endogenous NMN or treatment with a cell-permeant NMN-analog. In neurons, imaging documented mouse SARM1 activation preceded vincristine-induced axonal degeneration by hours. Library screening identified a derivative of nisoldipine as a covalent inhibitor of SARM1 that reacted with the cysteines, especially Cys311 in its ARM domain and blocked its NMN-activation, protecting axons from degeneration. The Cryo-EM structure showed that SARM1 was locked into an inactive conformation by the inhibitor, uncovering a potential neuroprotective mechanism of dihydropyridines.

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Section: Resultsmentioning

confidence: 93%

“…To quantify SARM1-dN, the protein was pulled down by BC2 nanobody (Bruce et al, 2017) Recombinant CD38 and N. crassa NADase were prepared as described previously. (Graeff et al, 1994, Munshi et al, 1997…”

Section: Preparation and Quantification Of The Enzymesmentioning

confidence: 99%

Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate

Huang

Cai

et al. 2021

eLife

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“…CD39 is an ectoenzyme (ecto-nucleotide triphosphate diphosphohydrolase 1, encoded by ENTPD1 gene) belonging to the family of ectonucleotidases which comprises ecto-5′-nucleotidase (NT5E)/CD73, CD38/NADase, NAD glycohydrolases, nucleoside diphosphate kinase, ecto-nucleotide pyrophosphate phosphodiesterases (E-NPPs), ecto-nucleoside triphosphate diphosphohydrolases (ENTPDases), and adenylate kinases [ 1 , 2 , 3 ].…”

Section: Adenosine Pathway and Cd39/cd73 Expression In The Tumor Microenvironmentmentioning

confidence: 99%

CD39 Regulation and Functions in T Cells

Timperi

Barnaba

2021

IJMS

101

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CD39 is an enzyme which is responsible, together with CD73, for a cascade converting adenosine triphosphate into adenosine diphosphate and cyclic adenosine monophosphate, ultimately leading to the release of an immunosuppressive form of adenosine in the tumor microenvironment. Here, we first review the environmental and genetic factors shaping CD39 expression. Second, we report CD39 functions in the T cell compartment, highlighting its role in regulatory T cells, conventional CD4+ T cells and CD8+ T cells. Finally, we compile a list of studies, from preclinical models to clinical trials, which have made essential contributions to the discovery of novel combinatorial approaches in the treatment of cancer.

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“…The relative rates of hydrolysis and cyclisation were also broadly similar to those with NAD (Fig. 2A), except that hSARM1 showed a lower cyclisation rate for NADP (≤1% of total NADP consumption) and CD38 a much higher cyclisation rate for NGD (~80% of total NGD consumption) [27,46]. These features, together with a selective inhibition by pyridine ribosides as described below, could be the basis of assays to distinguish CD38 and SARM1 in complex mixtures.…”

Section: Preliminary In Vitro Assays On Selected Multifunctional Nad(p)asesmentioning

confidence: 54%

Programmed axon death executor SARM1 is a multi-functional NAD(P)ase with prominent base exchange activity, all regulated by physiological levels of NMN, NAD, NADP and other metabolites

Angeletti

Amici

Gilley

et al. 2021

Preprint

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SARM1 is an NAD glycohydrolase and TLR adapter with an essential, prodegenerative role in programmed axon death (Wallerian degeneration). It has low basal NADase activity that becomes strongly activated by NAD precursor NMN. Very high levels of NAD oppose this activation, competing for the same allosteric site on SARM1′s regulatory ARM domain. Injury or diseases that deplete axons of NMNAT2, an essential enzyme converting NMN to NAD, cause SARM1 activation. The resulting NAD degradation by SARM1, combined with loss of NAD synthesis by NMNAT2, causes rapid depletion of axonal NAD. This NAD loss is widely assumed to mediate axon death and is consequently a key focus for therapeutic strategies for axonopathies. However, like other NAD(P) glycohydrolases, SARM1 has additional enzyme activities whose contributions, consequences and regulation need to be fully understood. Here, we compare the multiple actions and regulation of recombinant human SARM1 with those of two other NAD(P) glycohydrolases, human CD38 and Aplysia californica ADP ribosyl cyclase. We find that SARM1 has the highest transglycosidation (base exchange) activity of these enzymes at neutral pH and with some bases this dominates NAD(P) hydrolysis and cyclisation. Moreover, like its NADase and NADPase reactions, SARM1-mediated base exchange at neutral pH is activated by increases in the NMN:NAD ratio, which we show for the first time can act in the presence of physiological levels of both metabolites. We establish that SARM1 base exchange is the most likely physiological source of calcium mobilizing agent NaADP, and potentially of other NAD(P) analogues, which could contribute to axon and cell death. We also identify regulatory effects of free pyridine bases, of NADP and of nicotinic acid riboside (NaR) on SARM1 that represent further therapeutic opportunities. These data will help to pinpoint which of the multiple functions of SARM1 is responsible for axon degeneration and how it can be optimally targeted to block axon degeneration in disease.

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Enzymatic synthesis and characterizations of cyclic GDP-ribose. A procedure for distinguishing enzymes with ADP-ribosyl cyclase activity.

Cited by 232 publications

References 22 publications

Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate

Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate

CD39 Regulation and Functions in T Cells

Programmed axon death executor SARM1 is a multi-functional NAD(P)ase with prominent base exchange activity, all regulated by physiological levels of NMN, NAD, NADP and other metabolites

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