Nicotinamide mononucleotide (NMN) is a nucleotide that is most
recognized for its role as an intermediate of nicotinamide adenine
dinucleotide (NAD+) biosynthesis. Although the biosynthetic pathway of
NMN varies between eukaryote and prokaryote, two pathways are mainly
followed in case of eukaryotic human—one is through the salvage pathway
using nicotinamide while the other follows phosphorylation of
nicotinamide riboside. Due to the unavailability of a suitable
transporter, NMN enters inside the mammalian cell in the form of
nicotinamide riboside followed by its subsequent conversion to NMN and
NAD+. This particular molecule has demonstrated several beneficial
pharmacological activities in preclinical studies, which suggest its
potential therapeutic use. Mostly mediated by its involvement in NAD+
biosynthesis, the pharmacological activities of NMN include its role in
cellular biochemical functions, cardioprotection, diabetes, Alzheimer’s
disease, and complications associated with obesity. The recent
groundbreaking discovery of anti-ageing activities of this chemical
moiety has added a valuable essence in the research involving this
molecule. This review focuses on the biosynthesis of NMN in mammalian
and prokaryotic cells and mechanism of absorption along with the
reported pharmacological activities in murine model.wisepoqder Antiaging Powder
Nicotinamide mononucleotide (NMN) or
Nicotinamide-1-ium-1-β-D-ribofuranoside 5′-phosphate is a type of
bioactive nucleotide which is naturally formed by the reaction between a
phosphate group and a nucleoside containing ribose and nicotinamide
[1]. Generally, it exists in two anomeric forms namely alpha and beta.
The beta anomer is the active form between these two with a molecular
weight of 334.221 g/mol [2]. NMN is naturally abundant in various types
of food [3]. Vegetables like broccoli, cabbage contain 0.25–1.12 and
0.0–0.90 mg NMN/100 gm, fruits like avocado, tomato contain 0.36–1.60
and 0.26–0.30 mg NMN/100 gm, whereas raw beef has 0.06–0.42 mg NMN/100
gm [3]. NMN is also used as a substrate for prokaryotic enzymes like
NadM in Methanobacterium thermoautotrophicum, NadR in Haemophilus
influenza, NadM/Nudix in Francisella tularensis [4].
In human cells, NMN is available as a source of cellular energy. Not
long ago, this molecule was only known for its activity as an
intermediate in nicotinamide adenine dinucleotide (NAD+) biosynthesis.
During this biosynthetic process of NAD+, NMN acts as an important
substrate for enzymes like nicotinamide mononucleotide
adenylyltransferase 1 or NMNAT 1 of nuclear origin and NMNAT 3 of
mitochondrial origin that helps in the enzymatic conversion to NAD+ in
human [5]. Recently, preclinical studies have demonstrated diversified
pharmacological activities of NMN in cardiac and cerebral ischemia,
Alzheimer’s disease, diet- and age-induced type 2 diabetes, and obesity,
all of which are linked up to the deficiency of NAD+ [6,7,8].
Camacho-Pereira et al. have shown that an increased level of NAD+
consuming enzymes e.g., NAD+ dependent acetylase (Sirtuins), poly
ADP-ribose polymerase (PARP), NADase (CD38) contribute to the decline of
NAD+ with age [9]. In mammalian cells, CD38, a type of cell surface
NADase enzyme, causes breakdown of NAD+ to form nicotinamide and
(cyclic-)ADP-ribose [10]. On the other hand, expenditure of NAD+ helps
PARP to produce branched ADP-ribose polymers that help in DNA repairing
[11]. Another group of NAD+ consuming enzymes, sirtuins (SIRT 1-7)
performs different functions by consuming NAD+. Apart from
deacetylation, which is the most common NAD+ mediated function of
sirtuins, other functions like desuccinylase, demalonylase, lipoamidase,
and deglutarylase enzymatic activity are noteworthy that help in the
cellular adaptation of energy deficit and improvement of metabolic
function [12]. Administration of NMN can compensate for the deficiency
of NAD+ caused by these NAD+ consuming enzymes.
NMN shares similar properties like other NAD+ precursors-
nicotinamide riboside (NR), nicotinic acid, and nicotinamide [13].
Unlike NMN, nicotinic acid, and nicotinamide have several disadvantages
in terms of their therapeutic application. Nicotinamide may cause
hepatotoxicity or flushing, while a recent preclinical study suggests
that it resides in the rat body for a shorter period of time compared to
NMN [14,15]. Niacin or nicotinic acid is associated with adverse
effects like cutaneous flushing when administered as an immediate
release formulation whereas the sustained release formulations may cause
hepatotoxicity [16]. Among the NAD+ precursors, NR and NMN are
exceptions as fewer unfavorable side effects have been reported for
these two metabolites [17]. Moreover, nicotinamide riboside is also
orally bioavailable like NMN. Considering these, NMN could be proposed
as a preferable therapeutic option that can be supported by several
ongoing clinical trials (NCT03151239, UMIN000021309, UMIN000030609, and
UMIN000025739).
Here, in this review, the biosynthetic routes and absorption of NMN
are discussed followed by a comprehensive analysis of the preclinically
reported pharmacological properties with their underlying mechanism of
actions. This will provide an insight into the possibility of converting
these successful preclinical results for the treatment of human
diseases.
