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Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle
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NAD is an obligate co-factor for the catabolism of metabolic fuels in all cell types. However, the availability of NAD in several tissues can become limited during genotoxic stress and the course of natural aging. The point at which NAD restriction imposes functional limitations on tissue physiology remains unknown. We examined this question in murine skeletal muscle by specifically depleting Nampt, an essential enzyme in the NAD salvage pathway. Knockout mice exhibited a dramatic 85% decline in intramuscular NAD content, accompanied by fiber degeneration and progressive loss of both muscle strength and treadmill endurance. Administration of the NAD precursor nicotinamide riboside rapidly ameliorated functional deficits and restored muscle mass despite having only a modest effect on the intramuscular NAD pool. Additionally, lifelong overexpression of Nampt preserved muscle NAD levels and exercise capacity in aged mice, supporting a critical role for tissue-autonomous NAD homeostasis in maintaining muscle mass and function.
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“Reduced NAD+ levels in skeletal muscle of aged or Nampt deficient mice alter mitochondrial bioenergetics and impair muscle mass, strength and endurance49,50,52,53”
From Mitochondrial oxidative capacity and NAD+ biosynthesis are reduced in human sarcopenia across ethnicities (2019) · cites this paper as [52]
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BackgroundLactate Limits T Cell Proliferation via the NAD(H) Redox State
Quinn, W. J., Jiao, J., TeSlaa, T. A., Stadanlick, J. E., Wang, Z., Wang, L., Akimova, T., Angelin, A., Schäfer, P. M., Cully, M. D., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108500 · Cited by 376
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BackgroundInfluentialNicotinamide Riboside—The Current State of Research and Therapeutic Uses
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“Furthermore, NR could reverse the progressive wasting syndrome in skeletal muscle in mice lacking Nampt whilst restoring endurance, in as little as 1 week of treatment [111].”
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“The crucial role of cellular NAD+ is highlighted by the findings that ablation of the NAD+ biosynthetic enzyme NMNAT1 or NAMPT causes embryonic lethality [3, 4].”
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Ins and outs of the TCA cycle: the central role of anaplerosis
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“Muscle-specific NAMPT knockout mice showed an 85% decline in intramuscular NAD levels and accelerated age-related muscle degeneration resulting in a loss of strength and endurance.(19) Similarly, old wild-type mice also showed reduced levels of NAMPT and muscle decline.”
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“The increase in sleeping metabolic rate was due to an increase in FFM, suggesting that the primary effect of these findings could be an effect of NR on FFM. Interestingly, it has previously been shown that NAD + metabolism and homeostasis are involved in maintaining muscle mass (12).”
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Self-citationThe role of NAD+ metabolism and its modulation of mitochondria in aging and disease
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“Additionally, Nampt knockout mice models demonstrated that NAD + depletion in muscle leads to pro-gressivelossofmusclefunction,whileNRtreatmentrestoredmitochondrial functionandinducedmuscleremodelingandrestoration 255 .”
Nicotinamide adenine dinucleotide is transported into mammalian mitochondria
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Self-citationNAD precursors cycle between host tissues and the gut microbiome
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“Recent studies in mice employing stable isotope-labelled NR tracers have demonstrated that orally consumed NR is extensively metabolized to NAM and only very limited amounts of NAD+ in skeletal muscle are generated directly from NR (Frederick et al. 2016; Liu et al. 2018).”
BackgroundInfluentialTranscriptomic analyses reveal rhythmic and CLOCK-driven pathways in human skeletal muscle
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BackgroundNAD metabolism: Role in senescence regulation and aging
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“…and humans, appearing to be a conserved feature of aging across species (Braidy et al., 2011; Camacho-Pereira et al., 2016; Chini et al., 2020; Covarrubias et al., 2020; Frederick et al., 2016; Gomes et al., 2013; Guest et al., 2014; Mouchiroud et al., 2013; Tarragó et al., 2018; Zhu et al., 2015).”
BackgroundCow’s Milk Consumption and Health: A Health Professional’s Guide
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“Recent studies also suggest that another milk trace component, nicotinamide riboside, a niacin-derived substance (vitamin B3), may act on NAD metabolism and sirtuins, which in turn possess anti-aging properties (46).”
BackgroundRegulation of and challenges in targeting NAD+ metabolism
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“Interestingly, NMN supplementation normalized serum lactate levels in the FXN-KO mouse as compared with WT mice (Figure 6A), consistent with the literature, which shows reduced lactic acidosis in NMN-treated exercised mice (44).”
ResultLapatto, H. A. K., Kuusela, M., Heikkinen, A., Muniandy, M., van der Kolk, B. W., Gopalakrishnan, S., Sandvik, M., Schmidt, M. S., Heinonen, S., Saari, S., et al. (2023) · Science Advances · doi:10.1126/sciadv.add5163 · Cited by 136
“Currently, there is plenty of evidence for the efficacy of NR on muscle mitochondrial biogenesis in mice ( 7 – 11 ) but not in humans ( 19 , 22 ).”
Fletcher, R. S., Ratajczak, J., Doig, C. L., Oakey, L. A., Callingham, R., Xavier, G. D. S., Garten, A., Elhassan, Y., Redpath, P., Migaud, M. E., et al. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.05.011 · Cited by 125
“com skeletal muscle [38] but has not been explored in detail in the context of NRKs.”
BackgroundInfluentialSelf-citationThe chemistry of the vitamin B3 metabolome
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“, contractility and oxidative respiration) of skeletal muscle (Frederick et al. 2016; Agerholm et al. 2018), our findings highlight the importance of exercise training as an effective intervention to prevent aging-associated declines in skeletal muscle function.”
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“Recent studies demonstrate conditional as opposed to inducible Nampt deletion results in functional changes across a spectrum of cell and tissue types (Frederick et al., 2016; Lin et al., 2016; Rongvaux et al., 2008; Stein et al., 2014; Stromsdorfer et al., 2016).”
BackgroundNAD+ therapy in age-related degenerative disorders: A benefit/risk analysis
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“Illustrating this, administered NR is converted to Nam in the circulation before entering the cell [208, 227], whereas NMN is transformed extracellularly into NR, which then enters the cell and converts into NAD+ [227].”
BackgroundYamaguchi, S., Franczyk, M. P., Chondronikola, M., Qi, N., Gunawardana, S. C., Stromsdorfer, K. L., Porter, L. C., Wozniak, D. F., Sasaki, Y., Rensing, N. R., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1909917116 · Cited by 93
“In skeletal muscle, for example, loss of NAMPT triggers a dystrophic phenotype by impairing mitochondrial oxidative metabolism and ATP production (15), whereas PARP-2 inhibition enhances mitochondrial function and mitigates diet- or age-induced metabolic complications (16).”
BackgroundNMNAT2‐mediated NAD + generation is essential for quality control of aged oocytes
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“Moreover, lifelong overexpression of Nampt preserved muscle NAD levels and exercise capacity in aged mice (Frederick et al., 2016).”
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“In addition, the depletion of visfatin in mice leads to a decrease in intramuscular NAD synthesis and consequently induced fibre degeneration and progressive loss of strength and treadmill endurance muscle [178].”
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Emerging evidence for targeting mitochondrial metabolic dysfunction in cancer therapy
Zhu, Y., Dean, A. E., Horikoshi, N., Heer, C. D., Spitz, D. R., & Gius, D. R. (2018) · Journal of Clinical Investigation · doi:10.1172/jci120844 · Cited by 82
SIRT7: the seventh key to unlocking the mystery of aging
Raza, U., Tang, X., Liu, Z., & Liu, B. (2023) · Physiological Reviews · doi:10.1152/physrev.00044.2022 · Cited by 82
Nicotinamide Adenine Dinucleotide Metabolism and Neurodegeneration
Pehar, M., Harlan, B. A., Killoy, K. M., & Vargas, M. R. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7145 · Cited by 77
A need for NAD+ in muscle development, homeostasis, and aging
Goody, M. F., & Henry, C. A. (2018) · Skeletal Muscle · doi:10.1186/s13395-018-0154-1 · Cited by 76
“However, when extensor digitorum longus (EDL) muscle was repeatedly electrically stimulated ex vivo, force generation was significantly reduced [45].”
BackgroundResultInfluentialZhou, Q., Zhu, L., Qiu, W., Liu, Y., Yang, F., Chen, W., & Xu, R. (2019) · International Journal of Biological Sciences · doi:10.7150/ijbs.38487 · Cited by 76
“New strategies have been developed to empower the detection of subcellular NAD+ levels [62, 63, 65, 66].”
BackgroundTryptophan Metabolism: A Versatile Area Providing Multiple Targets for Pharmacological Intervention
Badawy, A. A.-B. (2019) · Egyptian Journal of Basic and Clinical Pharmacology · doi:10.32527/2019/101415 · Cited by 78
“Lack of NAD+ can result in oxidative damage, DNA damage, muscle degeneration, inflammatory responses and age-related diseases [204, 205].”
BackgroundWatson, A., Nong, Z., Yin, H., O’Neil, C., Fox, S., Balint, B., Guo, L., Leo, O., Chu, M. W. A., Gros, R., et al. (2017) · Circulation Research · doi:10.1161/circresaha.116.310022 · Cited by 72
Diverse therapeutic efficacies and more diverse mechanisms of nicotinamide
Song, S. B., Park, J., Chung, G. J., Lee, I. H., & Hwang, E. S. (2019) · Metabolomics · doi:10.1007/s11306-019-1604-4 · Cited by 73
Targeting CD38-dependent NAD+ metabolism to mitigate multiple organ fibrosis
Shi, B., Wang, W., Korman, B. D., Li, K., Wang, Q., Wei, J., Bale, S., Marangoni, R. G., Bhattacharyya, S., Miller, S. D., et al. (2020) · iScience · doi:10.1016/j.isci.2020.101902 · Cited by 72
Frailty index as a biomarker of lifespan and healthspan: Focus on pharmacological interventions
Palliyaguru, D. L., Moats, J. M., Germanio, C. D., Bernier, M., & de Cabo, R. (2019) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2019.03.005 · Cited by 75
Błaszczyk, J. W. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms24010543 · Cited by 74
“In particular, the NF-κB signaling pathway is associated with neuroinflammation and apoptosis [94,104].”
BackgroundHunt, L. C., Graça, F. A., Pagala, V., Wang, Y., Li, Y., Yuan, Z., Fan, Y., Labelle, M., Peng, J., & Demontis, F. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109971 · Cited by 74
“In support of this hypothesis, Nampt-deficient skeletal muscles display myofiber atrophy and reduced mass (Frederick et al., 2016).”
BackgroundZhang, M., & Ying, W. (2018) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7445 · Cited by 70
“NAD + deficiency is a key detrimental factor in aging Age-dependent decreases in NAD + levels have been found in the skeletal muscles (30, 86, 126), liver (126, 133), pancreas, and white adipose tissue (126) in animal models.”
InfluentialNAD+ in COVID-19 and viral infections
Zheng, M., Schultz, M. B., & Sinclair, D. A. (2022) · Trends in Immunology · doi:10.1016/j.it.2022.02.001 · Cited by 62
Shi, W., Hegeman, M. A., van Dartel, D. A. M., Tang, J., Suarez, M., Swarts, H., van der Hee, B., Arola, L., & Keijer, J. (2017) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201600878 · Cited by 62
“Furthermore, NR has been shown be converted to Nam before being absorbed or reaching tissues [67,68], where it is rapidly metabolized [69].”
BackgroundAging alters acetylation status in skeletal and cardiac muscles
Yeo, D., Kang, C., & Ji, L. L. (2020) · GeroScience · doi:10.1007/s11357-020-00171-7 · Cited by 63
“This finding agrees with several previous studies reporting age-related deficits of NAD+ in skeletal muscle (Koltai et al. 2010; Camacho-Pereira et al. 2016; Frederick et al. 2016; Schultz and Sinclair 2017; Tarragó et al. 2018).”
BackgroundResultInfluentialRe‐equilibration of imbalanced NAD metabolism ameliorates the impact of telomere dysfunction
Sun, C., Wang, K., Stock, A. J., Gong, Y., Demarest, T. G., Yang, B., Giri, N., Harrington, L. A., Alter, B. P., Savage, S. A., et al. (2020) · The EMBO Journal · doi:10.15252/embj.2019103420 · Cited by 67
“…by supplementation with NAD precursors ameliorate some age-related pathologies and increase life span and health span in animals (Fang et al , 2016; Frederick et al , 2016; Mills et NR supplementation (1 and 3 mM, respectively) on the proliferative capacity of DC fibroblasts during prolonged…”
Basse, A. L., Agerholm, M., Farup, J., Dalbram, E., Nielsen, J., Ørtenblad, N., Altıntaş, A., Ehrlich, A. M., Krag, T. O. B., Bruzzone, S., et al. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101271 · Cited by 61
Fukamizu, Y., Uchida, Y., Shigekawa, A., Sato, T., Kosaka, H., & Sakurai, T. (2022) · Scientific Reports · doi:10.1038/s41598-022-18272-y · Cited by 65
The therapeutic perspective of NAD+ precursors in age-related diseases
Iqbal, T., & Nakagawa, T. (2024) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2024.149590 · Cited by 68
Freeberg, K. A., Udovich, C. C., Martens, C. R., Seals, D. R., & Craighead, D. H. (2023) · The Journals of Gerontology Series A · doi:10.1093/gerona/glad106 · Cited by 69
The Metabolic Landscape in Osteoarthritis
Wu, X., Fan, X., Crawford, R., Xiao, Y., & Prasadam, I. (2022) · Aging and Disease · doi:10.14336/ad.2021.1228 · Cited by 65
“NAD levels are decreased in degenerative diseases, which may be due to the increase in NAD consumption enzymes [44].”
BackgroundNAD+ metabolism as a target for metabolic health: have we found the silver bullet?
Connell, N. J., Houtkooper, R. H., & Schrauwen, P. (2019) · Diabetologia · doi:10.1007/s00125-019-4831-3 · Cited by 60
Aman, Y., Frank, J., Lautrup, S., Matysek, A., Niu, Z., Yang, G., Shi, L., Bergersen, L. H., Storm‐Mathisen, J., Rasmussen, L. J., et al. (2019) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2019.111194 · Cited by 63
“…not only promote longevity, but it also has been shown to improve healthspan and prevent age-associated frailty in multiple laboratory models (Canto et al., 2015; Frederick et al., 2016; Lautrup et al., 2019b; Mills et al., 2016; Mitchell et al., 2018; Rajman et al., 2018; Yoshino et al., 2018).”
BackgroundNAD(H) in mitochondrial energy transduction: implications for health and disease
Walker, M. A., & Tian, R. (2018) · Current Opinion in Physiology · doi:10.1016/j.cophys.2018.03.011 · Cited by 59
Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity
Brady, P. N., Goel, A., & Johnson, M. A. (2019) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00038-18 · Cited by 58
“These effects are physiologically deleterious, leading to the degeneration of muscle cells (286).”
BackgroundNAD+ and NAFLD – caution, causality and careful optimism
Dall, M., Hassing, A. S., & Treebak, J. T. (2021) · The Journal of Physiology · doi:10.1113/jp280908 · Cited by 57
“To understand howNAD+ precursors exert their effects on peripheral tissues, recent studies have traced the fate of oral NR and NMN by labelling the compounds on both the nicotinamide and the ribose moieties (Frederick et al. 2016; Trammell et al. 2016a; Liu et al. 2018).”
BackgroundAge-Dependent Decline of NAD+—Universal Truth or Confounded Consensus?
Peluso, A. A., Damgaard, M. V., Mori, M. A., & Treebak, J. T. (2021) · Nutrients · doi:10.3390/nu14010101 · Cited by 61
“In the second study, a comparison was made between 4- and 24-month-old mice and showed the same pattern [73].”
ResultMitochondrial fidelity and metabolic agility control immune cell fate and function
Sack, M. N. (2018) · Journal of Clinical Investigation · doi:10.1172/jci120845 · Cited by 54
Leptin mediates the regulation of muscle mass and strength by adipose tissue
Collins, K. H., Gui, C., Ely, E. V., Lenz, K. L., Harris, C. A., Guilak, F., & Meyer, G. A. (2022) · The Journal of Physiology · doi:10.1113/jp283034 · Cited by 54
“Many pro-inflammatory adipokines are also secreted bymacrophages (Guilherme et al., 2019), and leptin, adiponectin and visfatin are all also produced by the muscle itself, where these factors are thought to exert autocrine action (Frederick et al., 2016; Krause et al., 2008;Wolsk et al., 2012).”
BackgroundSarcopenia, Aging and Prospective Interventional Strategies
Waltz, T. B., Fivenson, E. M., Morevati, M., Li, C., Becker, K. G., Bohr, V. A., & Fang, E. F. (2017) · Current Medicinal Chemistry · doi:10.2174/0929867324666170801095850 · Cited by 56
CD38 in the age of COVID-19: a medical perspective
Horenstein, A. L., Faini, A. C., & Malavasi, F. (2021) · Physiological Reviews · doi:10.1152/physrev.00046.2020 · Cited by 53
NAD+: A key metabolic regulator with great therapeutic potential
Sultani, G., Samsudeen, A., Osborne, B., & Turner, N. A. (2017) · Journal of Neuroendocrinology · doi:10.1111/jne.12508 · Cited by 54
Redox Signaling and Sarcopenia: Searching for the Primary Suspect
Foreman, N. A., Hesse, A. S., & Ji, L. L. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22169045 · Cited by 53
NAD+ Deficits in Age-Related Diseases and Cancer
Garrido, A., & Djouder, N. (2017) · Trends in cancer · doi:10.1016/j.trecan.2017.06.001 · Cited by 53
Poljšak, B., Kovač, V., Špalj, S., & Milisav, I. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032959 · Cited by 56
Endogenous nicotinamide riboside metabolism protects against diet-induced liver damage
Sambeat, A., Ratajczak, J., Joffraud, M., Sanchez-Garcia, J. L., Giner, M. P., Valsesia, A., Giroud‐Gerbetant, J., Valera‐Alberni, M., Cercillieux, A., Boutant, M., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12262-x · Cited by 51
Hyperglycemia-reduced NAD+ biosynthesis impairs corneal epithelial wound healing in diabetic mice
Li, Y., Li, J., Zhao, C., Yang, L., Qi, X., Wang, X., Zhou, Q., & Shi, W. (2020) · Metabolism · doi:10.1016/j.metabol.2020.154402 · Cited by 52
Metadata
- Authors
- Frederick, D. W., Loro, E., Liu, L., Davila, A., Chellappa, K., Silverman, I. M., Quinn, W. J., Gosai, S. J., Tichy, E. D., Davis, J. G., Mourkioti, F., Gregory, B. D., Dellinger, R. W., Redpath, P., Migaud, M. E., Nakamaru-Ogiso, E., Rabinowitz, J. D., Khurana, T. S., & Baur, J. A.
- Affiliations
- University of Pennsylvania (US)
- Princeton University (US)
- ChromaDex (United States) (US)
- Queen's University Belfast (GB)
- Corresponding author
- Baur, Joseph A.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-08
- Volume
- 24
- Issue
- 2
- Pages
- 269-282
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4985182
- OpenAlex
- W2499764253
- Cited by
- 367
- References
- 39
- Citations by year
- 2026: 16 · 2025: 43 · 2024: 34 · 2023: 38 · 2022: 49 · 2021: 44 · 2020: 40 · 2019: 39 · 2018: 35 · 2017: 25 · 2016: 4
- FWCI
- 19.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion)
- Funders
- Biotechnology and Biological Sciences Research Council (BB/N001842/1)
- National Institute on Aging (R01AG043483)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK019525, R01DK098656)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR050950, P30AR069619)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- NAD+ homeostasis, skeletal muscle degeneration, visfatin, NAD+ salvage pathway, nicotinamide riboside, muscle fiber degeneration, muscle strength, exercise capacity, aging, muscle mass, NAD+ depletion, genotoxic stress
- MeSH terms
- Administration, Oral, Aging, Animals, Biological Availability, Energy Metabolism, Glucose, Homeostasis, Inflammation, Mice, Inbred C57BL, Mitochondria, NAD, Necrosis, Niacinamide, Organ Size, Physical Conditioning, Animal, Pyridinium Compounds, Transcription, Genetic, Mice, Knockout, Muscle, Skeletal, Muscle Strength, Nicotinamide Phosphoribosyltransferase
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