Nicotinamide Deamidase from Mammalian Liver

Petrack, Barbara; Greengard, Paul; Craston, Ann; Sheppy, Fred

doi:10.1016/s0021-9258(18)97496-x

Cited by 62 publications

(7 citation statements)

References 13 publications

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“…5) pathways prior to its incorporation into the NAD metabolome. Our findings are consistent with early descriptions of mammalian de-amidase activity 37–, 39 and more recent work that integrates microbial and mammalian host NAD metabolism 44, 45 , though note that the direct NMN de-amidation by the gut microbiome as described here likely accounts for a small fraction of de-amidation of the overall NAD + metabolome. We also conclude that NMN cellular uptake most likely occurs following its dephosphorylation into NR 27 .…”

Section: Discussionsupporting

confidence: 92%

“…1a). Unlike mammals, where putative nicotinamide (Nam) and NMN deamidase activity 37–39 are poorly defined, bacteria present in the gut microbiome encode well-characterised deamidase enzymes such as PncC, which deamidates NMN into nicotinic acid mononucleotide (NaMN) for metabolism via the de novo pathway 40 . To test whether the gut microbiome alters the in vivo metabolism of orally administered NMN, we used mice that were exposed to a course of antibiotics to ablate the gut microbiome (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…NR is phosphorylated into NMN by NR kinases (NRK1/2) 27, 28 , and then adenylated into NAD + by NMNAT enzymes (NMNAT1-3) 29–34 , effectively bypassing NaAD, which is an intermediate of the Preiss- Handler and de novo pathways 35, 36 . There is evidence from over half a century ago for the existence of enzymes in mammals that are capable of deamidating nicotinamide 37–39 and NMN 38 , however the identity of these enzymes have not been revealed. In contrast, bacteria have a well-characterised NMN de-amidase enzyme, PncC 40 that prevents the accumulation of NMN, which can be toxic to bacteria through its inhibition of the bacterial DNA ligase 41–43 .…”

Section: Introductionmentioning

confidence: 99%

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Nicotinamide mononucleotide (NMN) deamidation by host-microbiome interactions

Kim

Chalmers

Smith

et al. 2020

Preprint

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Treatment with nicotinamide mononucleotide (NMN) is a prominent strategy to address the age-related decline in nicotinamide adenine dinucleotide (NAD+) levels for maintaining aspects of late-life health. It is assumed that exogenous NMN is directly incorporated into NAD+ in mammals by the canonical recycling pathway, however the need for NAD+ is conserved across evolution, including bacteria in the gut microbiome, which can deamidate NMN to nicotinic acid mononucleotide (NaMN). Here, we use strategic isotope labelling studies to demonstrate a role for the gut microbiome in deamidating orally delivered NMN into NaMN prior to its uptake and incorporation in mammals. Microbiome depletion increased the overall abundance of NAD metabolites, suggesting a competition relationship. Strikingly, treatment with labelled NMN increased the production of unlabelled NAD precursors, with a greater than 3-fold increase in endogenous NR levels in the gut of antibiotics treated animals upon labelled NMN treatment. These data suggest that exogenous NMN impacts the NAD metabolome through indirect means, rather than through its direct incorporation, including through the production of endogenous NR via an as-yet unidentified pathway, and demonstrate an important role for the gut microbiome in the assimilation of orally delivered NMN.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Nicotinamide mononucleotide (NMN) deamidation by host-microbiome interactions

Kim

Chalmers

Smith

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…5) pathways prior to its incorporation into the NAD metabolome. Our findings are consistent with early descriptions of mammalian de-amidase activity [39][40][41] and more recent work that integrates microbial and mammalian host NAD metabolism [47,48], though note that the direct NMN deamidation by the gut microbiome as described here likely accounts for only part of deamidation of the overall NAD + metabolome. We also conclude that NMN cellular uptake most likely occurs following its dephosphorylation into NR [29].…”

Section: Discussionsupporting

confidence: 92%

Host–microbiome interactions in nicotinamide mononucleotide (NMN) deamidation

et al. 2023

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The nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide mononucleotide (NMN) is a proposed therapy for age‐related disease, whereby it is assumed that NMN is incorporated into NAD+ through the canonical recycling pathway. During oral delivery, NMN is exposed to the gut microbiome, which could modify the NAD+ metabolome through enzyme activities not present in the mammalian host. We show that orally delivered NMN can undergo deamidation and incorporation in mammalian tissue via the de novo pathway, which is reduced in animals treated with antibiotics to ablate the gut microbiome. Antibiotics increased the availability of NAD+ metabolites, suggesting the microbiome could be in competition with the host for dietary NAD+ precursors. These findings highlight new interactions between NMN and the gut microbiome.

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“…T Xhe widespread occurrence of the enzyme nicotinamide deamidase (Preiss and Handler, 1958a,b;Imsande, 1961;Joshi and Handler, 1962;Bernheim, 1967;Pallini et al, 1965;Petrack et al, 1963Petrack et al, , 1965Kirchner et al, 1966;Marki and Greengard, 1966) and the possibility that control of the Preiss-Handler pathway of NAD biosynthesis may occur in vivo at this reaction (Greengard et al, 1963(Greengard et al, , 1965(Greengard et al, , 1969 have stimulated investigations into the physical, kinetic, structural, and control properties of the enzyme (Su et al, 1969). Of particular interest was the finding that nicotinamide deamidase from rabbit liver also catalyzes the hydrolysis of a variety of ester substrates (Su et al, 1969).…”

mentioning

confidence: 99%