Nicotinamide riboside/ja: Difference between revisions

The identification of Nicotinamide riboside (NR) as an NAD precursor in [[eukaryotes]] developed out of the study of [[pellagra]]. Pellagra was the first disease to be associated with NAD+ deficiency. It was linked to nutritional deficiency by [[Joseph Goldberger]] in 1914, and to deficiency of [[Niacin (substance)|niacin]] ([[Vitamin B3|vitamin B₃]]) by [[Conrad Elvehjem]] in 1937.  NAD+ (then called coenzyme I)  was shown to be extremely low in cases of pellagra, and NA and NAM were identified as molecular precursors in rebuilding NAD+ levels. Pellagra is now understood as a severe, chronic depletion of NAD+, which can be treated through diet.

Subsequent studies of NAD+ metabolism have identified regulatory pathways used by cells and tissues to maintain NAD+ availability. NAD+ and its precursors nicotinic acid (NA) and nicotinamide (NAM) have been shown to be vital cofactors in cellular [[Redox|oxidation/reduction reactions]] and [[Adenosine triphosphate|ATP]] synthesis.  Classic NAD+ synthesis pathways characterized in eukaryotes  include an eight-step ''de novo'' pathway from Trp and two pathways using the NAD+ precursors NA and NAM: a three-step NA-based pathway known as the Preiss-Handler pathway; and an NAM-based pathway involving the enzyme [[Nicotinamide phosphoribosyltransferase]] (NAMPT) and the formation of nicotinamide mononucleotide (NMN).

In 2004, a previously unknown pathway was reported when nicotinamide riboside (NR) was identified as an additional NAD+ precursor in [[eukaryotes]].

NR is now recognized as a form of [[Vitamin B3|vitamin B₃]] which can be found in both cow and human milk.

Once internalized into a cell, NR is rapidly phosphorylated by the activity of nicotinamide riboside kinase enzymes (NRK1 and NRK2)  to form nicotinamide mononucleotide (NMN), bypassing the previously known biosynthetic routes to NAD+ production.  NMN is then converted to NAD+ by NMN-adenylyltransferase (NMNAT).

Research in mammals indicates that NRK1 is a cytosolic protein, encoded by the ''Nmrk1'' gene. It is found in most tissues but predominantly in the liver and kidney. The NRK2 protein may be related to muscle tissue including cardiac muscle. It is encoded by the ''Nmrk2'' gene and appears to be more highly expressed in cases of metabolic stress or cellular damage.

Metabolic studies indicate that NAD+, once considered a stable molecule, is continuously turned over and used, requiring tight regulation to maintain metabolic homeostasis.  NR utilization in mammals may involve both exogenous dietary sources and endogenous salvage processes that recycle intermediates.  NR metabolism and the interactions of different NAD+ pathways continue to be studied. The NAM and NR pathways involve an amide group and are referred to as ‘amidated’ pathways. The pathways for ''de novo'' synthesis from tryptophan and from NA salvage are ‘deamidated’ pathways, which share a rate-limiting amidation enzyme NADsynthase1 (NADSYN). Disruptions or imbalances in NAD+ metabolism have been observed in many disease conditions, and the possibility of restoring NAD+ levels by administering NAD+ precursors is an area of interest for researchers.

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==Biosynthesis==

{{Main|Nicotinamide adenine dinucleotide#Biosynthesis}}

Nicotinamide riboside (NR) is now known to be an NAD+ precursor, involved in the biosynthetic pathways that convert B3 vitamins into NAD+. NAD+ is primarily synthesized in mammals de novo from tryptophan, through the Priess-Handler pathway from nicotinic acid (NA) or via a salvage pathway from nicotinamide (NAM).

[[File:NRK1 and NRK2 mediated biosynthesis pathway from NR to NAD+.png |450px|thumb|center|NRK1/2 mediated pathway from NR to NAD+]]

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==Commercialization==

[[ChromaDex]] licensed patents in July 2012, and began to develop a process to bring NR to market as TruNiagen. ChromaDex has been in a patent dispute with [[Elysium Health]] over the rights to nicotinamide riboside supplements since 2016.

==Safety designations==

In 2016, the U.S. Food and Drug Administration (FDA) has granted [[Generally recognized as safe]] (GRAS) status to ChromaDex for its preparation of nicotinamide riboside chloride (NRC, Niagen™). It was designated a new dietary ingredient (NDI) for use in dietary supplements by the U.S. Food and Drug Administration in 2015 and 2017. It was listed in Health Canada's Licensed Natural Health Products Database (LNHPD) in 2018.  The European Union has granted NRC a "New dietary ingredient" designation as a novel food pursuant to Regulation (EU) 2015/2283, as of 2019. It was authorized for use in food supplements by the EU in 2020. The EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) considered it as safe as pure nicotinamide for use in food for special medical purposes (FSMP) and total diet replacement for weight control (TDRWC) in adults as of 2021 but noted that further investigation would be required to establish safety for some other types of use.