Nicotinamide Mononucleotide Adenylyltransferase Activity in Human Erythrocytes

S, Sestini; Ricci, C; Micheli, Vanna; Pompucci, G

doi:10.1006/abbi.1993.1200

Cited by 10 publications

(7 citation statements)

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“…With respect to the organismal NAD homeostasis, blood seems to play a more neutral role, being mainly in charge of transport and delivery of NAD precursors. Taking into account that erythrocytes represent the most abundant blood cell type, the observed lowest rate of NAD turnover in blood can be explained by the lack of nuclei and mitochondria in mature red cells, resulting in a peculiar redistribution of NMNAT isozymes [46] , [62] and reduced total NMNAT activity [63] .…”

Section: Discussionmentioning

confidence: 99%

Metabolic Profiling of Alternative NAD Biosynthetic Routes in Mouse Tissues

et al. 2014

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NAD plays essential redox and non-redox roles in cell biology. In mammals, its de novo and recycling biosynthetic pathways encompass two independent branches, the “amidated” and “deamidated” routes. Here we focused on the indispensable enzymes gating these two routes, i.e. nicotinamide mononucleotide adenylyltransferase (NMNAT), which in mammals comprises three distinct isozymes, and NAD synthetase (NADS). First, we measured the in vitro activity of the enzymes, and the levels of all their substrates and products in a number of tissues from the C57BL/6 mouse. Second, from these data, we derived in vivo estimates of enzymes'rates and quantitative contributions to NAD homeostasis. The NMNAT activity, mainly represented by nuclear NMNAT1, appears to be high and nonrate-limiting in all examined tissues, except in blood. The NADS activity, however, appears rate-limiting in lung and skeletal muscle, where its undetectable levels parallel a relative accumulation of the enzyme's substrate NaAD (nicotinic acid adenine dinucleotide). In all tissues, the amidated NAD route was predominant, displaying highest rates in liver and kidney, and lowest in blood. In contrast, the minor deamidated route showed higher relative proportions in blood and small intestine, and higher absolute values in liver and small intestine. Such results provide the first comprehensive picture of the balance of the two alternative NAD biosynthetic routes in different mammalian tissues under physiological conditions. This fills a gap in the current knowledge of NAD biosynthesis, and provides a crucial information for the study of NAD metabolism and its role in disease.

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Section: Discussionmentioning

confidence: 99%

Metabolic Profiling of Alternative NAD Biosynthetic Routes in Mouse Tissues

et al. 2014

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“…In the marine alga Acetabularia mediterrunea (Bannwarth et al, 1969) and in rabbit dorsal root ganglion cells (Kato and Lowry, 1973) it was found present in the cytoplasm and virtually absent in the nuclei. Furthermore, NMN adenylyltransferase has also been detected in human red blood cells (Sestini et al, 1993) and recently clearly demonstrated in rat liver mitochondria1 matrix (Barile et al, 1996). NMN adenylyltransferase has been only partially purified from prokaryotes, including E. coli (Dahmen et al.…”

Section: B N M N Adenylyltransferasementioning

confidence: 99%

Enzymology of Nad ⁺ Synthesis

Magni

Amici

Emanuelli

et al. 1999

Advances in Enzymology - And Related Areas of Molecular Biology

195

194

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“…In the human red blood cell, NAD + synthesis is limited to a NAD + salvage pathway that utilizes either exogenously acquired nicotinic acid (Na) or nicotinamide (Nam), which are collectively known as niacin or vitamin B 3 [19]. Na is converted to NAD + through the Preiss-Handler pathway in three steps - Na is first converted into nicotinate mononucleotide (NaMN) via the nicotinic acid phosphoribosyltransferase (NAPRT), then to nicotinate adenine dinucleotide (NaAD) via the nicotinamide mononucleotide adenylyltransferase (NMNAT) and finally to NAD + via the glutamine-dependent NAD + synthetase (NADSYN) [20], [21] - while Nam can be converted to NAD + in a two-step pathway found in higher eukaryotic organisms involving nicotinamide riboside kinase (NRK) and NMNAT (Figure 1A) [22]. In the de novo synthesis pathway, prokaryotes can utilize aspartate to feed into the synthesis of NAD + , whereas eukaryotes rely on intermediates generated from the breakdown of tryptophan [23].…”

Section: Introductionmentioning

confidence: 99%

Targeting NAD+ Metabolism in the Human Malaria Parasite Plasmodium falciparum

et al. 2014

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Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite utilized as a redox cofactor and enzyme substrate in numerous cellular processes. Elevated NAD+ levels have been observed in red blood cells infected with the malaria parasite Plasmodium falciparum, but little is known regarding how the parasite generates NAD+. Here, we employed a mass spectrometry-based metabolomic approach to confirm that P. falciparum lacks the ability to synthesize NAD+ de novo and is reliant on the uptake of exogenous niacin. We characterized several enzymes in the NAD+ pathway and demonstrate cytoplasmic localization for all except the parasite nicotinamidase, which concentrates in the nucleus. One of these enzymes, the P. falciparum nicotinate mononucleotide adenylyltransferase (PfNMNAT), is essential for NAD+ metabolism and is highly diverged from the human homolog, but genetically similar to bacterial NMNATs. Our results demonstrate the enzymatic activity of PfNMNAT in vitro and demonstrate its ability to genetically complement the closely related Escherichia coli NMNAT. Due to the similarity of PfNMNAT to the bacterial enzyme, we tested a panel of previously identified bacterial NMNAT inhibitors and synthesized and screened twenty new derivatives, which demonstrate a range of potency against live parasite culture. These results highlight the importance of the parasite NAD+ metabolic pathway and provide both novel therapeutic targets and promising lead antimalarial compounds.

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Nicotinamide Mononucleotide Adenylyltransferase Activity in Human Erythrocytes

Cited by 10 publications

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Metabolic Profiling of Alternative NAD Biosynthetic Routes in Mouse Tissues

Metabolic Profiling of Alternative NAD Biosynthetic Routes in Mouse Tissues

Enzymology of Nad ⁺ Synthesis

Targeting NAD+ Metabolism in the Human Malaria Parasite Plasmodium falciparum

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Nicotinamide Mononucleotide Adenylyltransferase Activity in Human Erythrocytes

Cited by 10 publications

References 0 publications

Metabolic Profiling of Alternative NAD Biosynthetic Routes in Mouse Tissues

Metabolic Profiling of Alternative NAD Biosynthetic Routes in Mouse Tissues

Enzymology of Nad + Synthesis

Targeting NAD+ Metabolism in the Human Malaria Parasite Plasmodium falciparum

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Enzymology of Nad ⁺ Synthesis