ArticlePloS one2012
Glutamine versus ammonia utilization in the NAD synthetase family.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 42 citations in OpenAlex.
- Glutamine Supplementation and Exercise: A Narrative Review of Biochemical Mechanisms and Timing Strategies.Medicina (Kaunas, Lithuania) · 2026Review
- Structure of a putative terminal amidation domain in natural product biosynthesis.Structure (London, England : 1993) · 2025Article
- NADMicrobes and environments · 2023Article
- Inhibition of the NAD salvage pathway in schistosomes impairs metabolism, reproduction, and parasite survival.PLoS pathogens · 2020Article
- NADThe Journal of biological chemistry · 2020Article
- Different ways to transport ammonia in human and Mycobacterium tuberculosis NADNature communications · 2020Article
- Bi-allelic Mutations in NADSYN1 Cause Multiple Organ Defects and Expand the Genotypic Spectrum of Congenital NAD Deficiency Disorders.American journal of human genetics · 2020Article
- The emergence of the nicotinamide riboside kinases in the regulation of NAD+ metabolismJournal of molecular endocrinology · 2018Review
- Hyperthermophilic Archaeon Thermococcus kodakarensis Utilizes a Four-Step Pathway for NADJournal of bacteriology · 2018Article
- Kinetics and structural features of dimeric glutamine-dependent bacterial NADThe Journal of biological chemistry · 2018Article
- Pyrroline-5-carboxylate reductase 1 promotes proliferation and inhibits apoptosis in non-small cell lung cancer.Oncology letters · 2018Article
- High protein intake is associated with low plasma NAD+ levels in a healthy human cohort.PloS one · 2018Article
- Metabolism Dealing with Thermal Degradation of NADJournal of bacteriology · 2017Article
- Design, synthesis, and evaluation of substituted nicotinamide adenine dinucleotide (NADBioorganic & medicinal chemistry letters · 2017Article
- Gender differences in white matter pathology and mitochondrial dysfunction in Alzheimer's disease with cerebrovascular disease.Molecular brain · 2016Article
- Mycobacterial nicotinate mononucleotide adenylyltransferase: structure, mechanism, and implications for drug discovery.The Journal of biological chemistry · 2015Article
- Systematic genome assessment of B-vitamin biosynthesis suggests co-operation among gut microbes.Frontiers in genetics · 2015Article
- Proline metabolism and cancer: emerging links to glutamine and collagen.Current opinion in clinical nutrition and metabolic care · 2015Review
- Metabolic and bactericidal effects of targeted suppression of NadD and NadE enzymes in mycobacteria.mBio · 2014Article
- Article
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Authors and funding
6 authors at 4 institutions in 3 countries.
Funding
Abstract
NAD is a ubiquitous and essential metabolic redox cofactor which also functions as a substrate in certain regulatory pathways. The last step of NAD synthesis is the ATP-dependent amidation of deamido-NAD by NAD synthetase (NADS). Members of the NADS family are present in nearly all species across the three kingdoms of Life. In eukaryotic NADS, the core synthetase domain is fused with a nitrilase-like glutaminase domain supplying ammonia for the reaction. This two-domain NADS arrangement enabling the utilization of glutamine as nitrogen donor is also present in various bacterial lineages. However, many other bacterial members of NADS family do not contain a glutaminase domain, and they can utilize only ammonia (but not glutamine) in vitro. A single-domain NADS is also characteristic for nearly all Archaea, and its dependence on ammonia was demonstrated here for the representative enzyme from Methanocaldococcus jannaschi. However, a question about the actual in vivo nitrogen donor for single-domain members of the NADS family remained open: Is it glutamine hydrolyzed by a committed (but yet unknown) glutaminase subunit, as in most ATP-dependent amidotransferases, or free ammonia as in glutamine synthetase? Here we addressed this dilemma by combining evolutionary analysis of the NADS family with experimental characterization of two representative bacterial systems: a two-subunit NADS from Thermus thermophilus and a single-domain NADS from Salmonella typhimurium providing evidence that ammonia (and not glutamine) is the physiological substrate of a typical single-domain NADS. The latter represents the most likely ancestral form of NADS. The ability to utilize glutamine appears to have evolved via recruitment of a glutaminase subunit followed by domain fusion in an early branch of Bacteria. Further evolution of the NADS family included lineage-specific loss of one of the two alternative forms and horizontal gene transfer events. Lastly, we identified NADS structural elements associated with glutamine-utilizing capabilities.
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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.