|
 Pdf file on Molecular properties, functions, and potential
applications of NAD kinases
Feng Shi1*, Yongfu Li2,
Ye Li1, and Xiaoyuan Wang1
1State Key Laboratory of Food Science and Technology, 2School of Food Science,
*Correspondence address. Tel/Fax: +86-510-85329236;
E-mail: [email protected]
NAD kinase
catalyzes the phosphorylation of NAD(H) to form
NADP(H), using ATP as phosphoryl donor. It is the
only key enzyme leading to the de novo NADP1/ NADPH biosynthesis. Coenzymes
such as NAD(H) and NADP(H) are known for their important functions. Recent
studies have partially demonstrated that NAD kinase
plays a crucial role in the regulation of NAD(H)/ NADP(H) conversion. Here, the
molecular properties, physiologic functions, and potential applications of NAD kinase are discussed.
Keywords NAD kinase; NAD+/NADH; NADP+/NADPH;
coenzyme metabolism
Received: November 12, 2008 Accepted: February 12, 2009
Introduction
NAD kinase phosphorylates
NAD(H) to form NADP(H), using ATP as a phosphoryl
donor (Fig. 1). This is the only pathway for the de
novo NADP+/ NADPH
biosynthesis, thus has an important function in supplying NADP+/NADPH and
regulating the level of NAD(H)/NADP(H). As NADP(H) is the crucial coenzyme for
many cellular processes in living organisms, such as NADPH-dependent reductive
anabolic pathways, signal transduction, and anti-oxidative defense system, NAD kinase may be critical for the normal cellular functions.
Several studies have indicated that NAD kinase is essential
for the survival of certain organisms, such as Mycobacterium tuberculosis
[1], Bacillus
subtilis [2], Escherichia coli [3], and Salmonella
enterica [4]. Homolog genes of NAD kinase
can be found in all the sequenced genomes of living organisms, including
prokaryotes and eukaryotes, with the exception of the intracellular parasite Chlamydia
trachomatis [4]. In most organisms, there is only one NAD kinase, but in some organisms several NAD kinase isozymes may exist. For
example, two NAD kinases, NadF
and NadG, were found in Salmonella typhimurium [5]; two NAD kinases isozymes with distinctive catalytic mechanisms and Km values were presented in Euglena
gracilis [6]. There are three NAD kinases
in yeast Saccharomyces cerevisiae, with Pos5p
in mitochondrial matrix, and Utr1p and Yef1p in cytoplasm [7,8]. These three
NAD kinase isozymes have
different functions due to particular subcellular
locations, with some functions weakly rescued by their isozymes
[8,9]. Three NAD kinases, NADK1, NADK2, and NADK3,
were also found in Arabidopsis thaliana. NADK1 is calmodulin
(
Catalytic and Structural Properties of NAD Kinases
As NAD kinase is a crucial
enzyme that regulates the levels of NAD(H)/NADP(H) in the metabolic pathways, enzymatic
properties of NAD kinases from several organisms have
been studied in the past decade. This includes the study of in
vitro catalytic properties of natural or recombinant enzymes, such as their
substrate specificity and modulators, and their structural properties,
especially the active center structure and molecular conformation.
Catalytic properties
Substrate specificity
Although it has been proved that NAD kinases
from all living organisms are highly conserved, differences in the enzymatic
properties from various organisms may exist. One of the critical differences is
the substrate specificity, including the phosphoryl
donor and phosphoryl acceptor. For example, ATP–NAD kinase utilizes ATP as the
sole phosphoryl donor for NAD(H) phosphorylation;
NTP-NAD kinase uses ATP as well as some other
nucleoside triphosphates such as GTP, CTP, UTP, and
ITP; poly(P)/NTP-NAD kinase utilizes NTP as well as
inorganic polyphosphates [ poly(P)]. NAD+ kinase (EC According to the phosphoryl
acceptor of NAD kinases, some studies reported that
NAD kinases from Gram-negative bacteria (e.g. E.
coli and Sphingomonas sp. A1)
could only phosphorylate NAD+,
whereas NAD kinases from Gram-positive bacteria (e.g.
M. flavus and M. tuberculosis) and three NAD kinases of eukaryotic S. cerevisiae
used NAD+ and NADH as phosphoryl acceptor [21,27], indicating that the phosphoryl acceptor specificity of NAD kinases
may also depend on the organisms [12].
In vitro allosteric regulation mode and
regulators
Besides the remarkable differences in substrate
specificity, obvious diversities in regulatory mode also exist among NAD kinases from different sources. The initial purpose of the
study on NAD kinase was to understand its regulatory
properties, and speculate its influence on NAD(H)/NADP(H) metabolic flux. Such
studies showed that purified NAD kinases from some
organisms were indeed regulated in vitro by effectors such as NAD(H)
or NADP(H), but difference in the regulatory mode existed.
In Gram-negative bacteria, NADH and NADPH are potent allosteric negative modulators of NAD kinases
in both E. coli [28] and S. enterica [4],
whereas NADP+ and NADPH are negative modulators of NAD kinase in Sphingomonas sp. A1
[21]. In Gram-positive bacteria, the activity of NAD kinases
from both Bacillus licheniformis [29] and B. subtilis [17] is inhibited intensively by NADP+; the
activity of NAD kinase from M. tuberculosis is also
repressed greatly by NADP+ [30], but that from both M. tuberculosis H37Rv and M. flavus is inhibited by low concentration of NADPH [14]. For the
three NAD kinases of eukaryotic S. cerevisiae, Utr1p is inhibited by NADP+, NADH,
and most strongly by NADPH [22]; Yef1p is weakly inhibited by NADH and NADPH
[8]. The precursors of NAD+ biosynthesis, such as quinolinate
and nicotinic acid, do not influence NAD kinase
activity in general. But NadG, one of the NAD kinases of S. typhimurium, is
inhibited by quinolinate [5], whereas B. subtilis NAD kinase is activated by quinolinate [17].
As in vitro regulatory patterns of NAD kinases differ distinctively among microbes, the control of
enzymatic activity, particularly through allosteric
regulation, as well as the regulatory mechanism of NAD kinase
to the NAD(H)/NADP(H) metabolic flux has not been elucidated. The growing
environment and physiologic status of different organisms, as well as the
consequent cellular form and level of cofactors, may also lead to the
divergence of regulatory mode of NAD kinases,
especially when several NAD kinase isozymes are presented. Different from bacterial NAD kinases, some of the higher plant NAD kinases
are regulated by
Structural properties
NAD kinases of different
organisms show sequence similarity. For example, the identity of E.
coli NAD kinase with that of S. enterica
is 96%,
but with that of M. tuberculosis is 32%, and with Pos5p of S. cerevisiae is 33%. All characterized NAD kinases
show homooligomer structures, but the molecular size
and number of subunit show some differences. The molecular size of subunit from
prokaryotes was approximately 30–35 kDa, e.g. 30 kDa hexamer from E. coli [20], 32 kDa
dimmer from Sphingomonas sp. A1 [21], 33–35 kDa tetramer or dimer from M. tuberculosis [14,30,31], 34 kDa dimmer from M. flavus [14], and
37 kDa tetramer from archaeon
P. horikoshii [19]. The molecular size of subunit from eukaryotes
varied widely, e.g. 60 kDa octamer
of Yef1p and 60 kDa hexamer
of Utr1p from S. cerevisiae [8,22], 32
kDa octamer from Candida
utilis [32], 34 kDa octamer from pigeon liver [33], and 49 kDa
tetramer from human [24]. However, the molecular size of subunit from the archaeon M. jannaschii was much
larger as 64 kDa, since two distinguishable regions
of NAD kinase and NADP phosphatase
existed [18], and the sequence showed a low level of identity to those of E.
coli (31%) and
of M.
tuberculosis (29%) [18]. The oligomeric
assembly of NAD kinases may be due to their catalytic
mechanism.
To realize the reasons for the differences of catalytic
properties, conserved sequences and active center residues of some NAD kinases were analyzed recently [34]. There are three
conserved sequences in the primary structure of NAD kinases,
that is, the GGDG motif, NE/ D short motif, and conserved domain II rich in glycines (Fig. 2), all of which are responsible
for substrate binding and activation. The study by Labesse
et
al. [35]
indicated that NAD kinase belonged to a new superfamily of kinases, which
included 6-phosphofructokinases (PFKs), diacylglyceride kinases, and sphingosine kinases. These
enzymes had a common fold and a conserved GGDGT motif, and also a common
strategy for catalysis. However, the study by Poncet-Montange
et
al. [36] on Listeria monocytogenes NAD kinase showed that NAD kinase
(LmNADK1) and PFKs used the central Asp of DDGDT
motif differently. While Asp residue chelated the
catalytic Mg2+ in PFKs to activate ATP, it
absorbed the 2′-hydroxyl proton of adenosine ribose of NAD+ in LmNADK
to activate NAD+. For the two subsets of NADH
and NAD+ kinases, the
study of primary and tertiary structures demonstrated that phosphor acceptor
specificity was determined by the second amino acid residue in the N-terminal
upstream of the conserved domain II (Fig. 2). Charged or hydrophobic amino
acid residues in the corresponding position gave the stringent substrate
specificity of NAD+ kinases to NAD+, whereas
polar amino acid or Gly residue in the corresponding
position was a prerequisite for the expression of NADH kinase
activity [27].
In recent years, molecular conformation of NAD kinases has been studied in order to understand their
catalytic mechanisms. Studies showed that each subunit of M.
tuberculosis NAD kinase consisted of an
N-terminal a/b domain and a C-terminal 12-stranded b sandwich domain, connected by swapped bstrands [31]. A flexible loop in its active center was involved in the intersubunit contact and probably related to the NAD+ binding of the other subunit
[37]. Intersubunit contact was significant in
creating substrate binding sites and expressing NAD+and NADH-kinase activities [12]. NAD kinase
of hyperthermophilic eubacterium
Thermotoga maritime was also
folded into two distinct domains: the N-terminal a/b domain and
the unique middle b-sandwich architecture [38].
For the NAD kinase of hyperthermophilic
archaeon Archaeoglobus fulgidus, the AMP portion of substrate ATP molecule used the same
binding site as the nicotinamide ribose portion of
product NADP+, i.e. Tyr158 of domain II,
whereas the conserved GGDG loop formed hydrogen bonds with the pyrophosphate
group of ATP and the 2′ phosphate group of NADP+ [39]. The Asp residue of GGDG motif in LmNADK1 activated
the phosphor acceptor NAD+ and then made it accept the terminal phosphate residue of
Mg2+–ATP to form NADP+ [36]. Three-dimensional
structure of NAD kinases also showed that they are homooligomers.
Roles of NAD Kinases in
NAD(H)/NADP(H) Metabolism
As the most important coenzymes in living organisms,
NAD(H) and NADP(H) participate in more than 300 different oxidative–reductive reactions [40], their importance in substance
metabolism and energy metabolism has long been known. NAD(H) is primarily
involved in oxidative catabolic reactions, whereas NADP(H) participates in
reductive anabolic reactions. Many studies have also proved their roles in a
plethora of different biochemical processes. NAD participates in ADP-ribosylation of proteins, which is further involved in the
regulation of several processes such as DNA repair [41], as well as in the
synthesis of B12 [42] and deacetylation of protein
[43]. However, NADP participates in defense against oxidative stress [44], and
is a substrate for the synthesis of nicotinic acid adenine dinucleotide
phosphate which is a potent intracellular Ca2+-mobilizing
messenger. Owing to these significant and distinguishable function of NAD(H)
and NADP(H), their metabolism and intracellular balance must be tightly
regulated. NAD kinase is a critical enzyme for the
regulation of NAD(H) and NADP(H) balance (Fig. 3). It
creates the only obligate route for the de novo biosynthesis
of NADP(H) in all living organisms. As many NAD kinases
are allosteric enzymes, the NAD(H) and NADP(H)
balance might be directly regulated by NAD kinase.
Although the mechanisms regulating NAD(H)/ NADP(H) metabolic flux are not fully
elucidated, the significance of NAD kinase has been
well accepted, especially the central role of NAD kinase
in NADPH supplying network.
Central role of NAD kinase
in NADPH supply network
The supply of NADPH in living systems can be fulfilled
through several one-step enzymatic reactions (Fig. 3). The
first reaction is catalyzed by NADP+-dependent
dehydrogenases, such as isocitrate
dehydrogenase (ICDH), glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconate dehydrogenase (6PGDH), malate
enzyme, and glutamate dehydrogenase (GDH) [45,46].
The second reaction is catalyzed by pyridine nucleotide transhydrogenase
that transfers a hydride from NADH to NADP+ with the concurrent production
of NADPH, powered by the proton motive force [47]. The third reaction is
mediated by NADH kinase which directly phosphorylates NADH to form NADPH [48]. Influenced by the
intracellular coenzyme levels, quick supply of NADPH is usually ensured by the
cooperation of NAD kinase and NADP+-dependent
dehydrogenase (e.g. pentose phosphate enzyme
systems), such as in the ocular lens [49]. However, continuous supply of NADPH
depends on the cyclic metabolic networks. Recently, studies on the survival
strategies of Pseudomonas fluorescens
in
oxidative environment proved that NAD kinase was
requisite for the controlling of NAD(H)/NADP(H) balance, especially the
sufficient supply of NADPH, to adapt to environmental variance [50–52], suggesting the critical role of NAD kinase on adjusting NAD(H)/ NADP(H) coenzyme in the
metabolic networks. For example, when P. fluorescens was
exposed to oxidative stress triggered by menadione
insult, some enzymes involved in disparate metabolic modules could converge to
create a metabolic network in order to convert NADH into NADPH. At the same
time, NAD kinase (NADK), malic
enzyme (ME), together with pyruvate carboxylase (PC) of gluconeogenesis,
and malate dehydrogenase
(MDH) of tricarboxylic acid cycle were upregulated, ensuring the cyclic supplying of NADPH from
NADH. Meanwhile, the phosphoenolpyruvate carboxykinase (PEPCK) was downregulated,
but the pyruvate kinase
(PK) was upregulated and its activity was enhanced.
The regulations on PEPCK and PK could prevent pyruvate
and oxaloacetate from fluxing into gluconeogenesis pathway, and enhance the acceleration of oxaloacetate which could contribute to NADH oxidation.
Further more, the enhanced activity of isocitrate lyase (ICL) and malate synthase (MS) of glyoxylate cycle
could promote the supplying of malate, which in turn
could contribute to NADP+ reduction. All these regulation can result in effective
synthesis of NADPH [50] (Fig. 4).
Role of NAD kinases
and NADP phosphatases in the conversion of NADP(H) to
NAD(H) Different from NAD(H) phosphorylation, the
reverse process of NADP(H) dephosphorylation has not
been well studied, although it might influence the NAD(H)/ NADP(H) metabolism
and balance. Recently, NADP phosphatase has been
found in several organisms. For example, in the hyperthermophilic
archaeon M. jannaschii, MJ0917
has activities of both NAD kinase and NADP phosphatase, it could supply NADP+ and also prevent excess
accumulation of NADP+ [18]. Another inositol monophosphatase MJ0109 also has NADP phosphatase
activity [53]. AF2372 from the hyperthermophilic archaeon Archaeoglobus fulgidus has NADP phosphatase activity
in addition to fructose-1,6-bisphosphatase activity [53]. In eubacterium E. coli, the 3′-phosphoadenosine
5′-phosphate phosphatase (CysQ)
exhibits NADP phosphatase activity in
vitro, but not in
vivo [53].
Although NAD kinase has a
central role in the NAD(H)/NADP(H) metabolic network, especially in the
one-step and cyclic supplying of NADPH, its regulatory mechanism has not been
well elucidated. Because of the diversity and complexity of NAD(H)/NADP(H)
metabolic pathways, NAD kinase would exhibit pleiotropic regulation for a number of reactions and
pathways through controlling of NAD(H)/NADP(H) conversion. Studies on the
cofactor engineering have proved that metabolic flux can be effectively
regulated through controlling of key cofactors. For example, shifting from homolactic to mixed-acid fermentation in Lactococcus lactis
could be
modulated by the decrease of NADH/ NAD+ ratios under aerobic conditions
[54]. However, the application of NAD kinase in
cofactor engineering has not been reported.
Roles of NAD Kinase in
Anti-Oxidative System
Based on the elucidation of gene or genomic information
in numerous living organisms, the anti-oxidative function of NAD kinase has been proved. For example, in S. enterica [4] and in the mitochondria of S. cerevisiae
[7,8,23,55],
NAD kinase plays a major role in protecting living
cells against oxidative stress. In human cells and in rats, NAD kinase controls NADPH concentration, which in turn
influences the cellular anti-oxidative defense function [56,57].
NADPH is vital in intracellular anti-oxidative defense
system for most organisms, and its central role in the resistance of oxidative
stress has been proved [51]. NADPH can provide electrons for reductive
repairing and deoxyribose synthesis. It is also a
universal cofactor for numerous enzymes participating in detoxification
reactions, including glutathione reductase [58], thioredoxin reductase and cytochrome P450 reductase. These
enzymes promote anti-oxidants, such as glutathione to be at active reducing
form, thus ensure the activity of glutathione peroxidase.
Too much NADH can lead to the release of Fe2+ to accumulate reactive oxygen
species by respiratory chain or oxidases, suggesting
NADH could be a pro-oxidant [5,59].
Living systems have evolved numerous one-step strategies
for the genesis of NADPH (Fig. 3). However, as these one-step
reactions cannot be performed circularly, they are not so effective while
operated separately. Thus when cells are exposed to oxidative stress,
activities of key enzymes in many metabolic pathways are regulated in order to
promote conversion of pro-oxidant NADH into antioxidant NADPH. Through the
regulation of these ‘housekeeping’ metabolic
networks, more effective anti-oxidation will be obtained by producing NADPH
with concomitant expense of NADH (Fig. 4). Thus,
NAD kinase is required and crucial in either the
quick one-step NADPH generator or the more effective cyclic NADPH generator.
Although NADP+-dependent dehydrogenases
can also generate NADPH and may show positive function on anti-oxidation, they
depend on a constant supply of substrate and further procession of product,
hence may not be fully self-sustaining and cannot constantly supply NADPH. For
example, although G6PDH of pentose phosphate pathway also had anti-oxidation
function, it was restricted by its substrate glucose-6-phosphate and product
6-phosphogluconate [60]. Although mitochondrial NADP+-dependent
isocitrate dehydrogenase IDPm has an important function in the control of
mitochondrial redox balance and cellular defense
against oxidative damage [45], it depends on the support of tricarboxylic
acid cycle. Therefore, NAD+ kinase or NADH kinase activity is required for sustaining the NADPH level
to regenerate the anti-oxidative system.
Physiological Function of NAD Kinase
in Plants
Plant NAD kinases were brought
into sight earlier than those of microorganisms mainly because of the
possession of both CaM-independent and CaM-regulated NAD kinase isoforms in plants. Whereas in microorganisms and animal
cells, NAD kinase activity is not dependent on CaM-dependent NAD kinase is
essential for survival of plant under difficult conditions and for protecting
plants against invading pathogens. CaM-dependent NAD kinase could play a metabolic role and participate in Ca2+-mediated
cellular defense against invading pathogens in plants by helping to provide reductant for the NADPH-dependent oxidative burst [65].
Increasing levels of NAD synthetase and NAD kinase of rice through dihydroflavonol-4 reductase could result in the increased level of NADP(H),
conferring the prevention of induced cell death in plants caused by hydrogen
peroxide and bacterial disease [66]. As green beans were subject to coldshock, Ca2+/CaM-dependent
NAD kinase activity was increased, which is closely
related with proline metabolism, indicating their
importance in cold acclimation of green bean plants [67].
In the chloroplast of plants, NAD kinase
plays a vital role in energy transduction [11,68]. For example, one of the
three NAD kinase isozymes
of A.
thaliana, NADK2, was a chloroplast NAD kinase that can
bind Ca2+/CaM
[10]. The NADK2 deletion mutant displayed hypersensitivity to
environmental stresses provoking oxidative stress, such as UVB, drought, heat
shock, and salinity, its chlorophyll content was also reduced, indicating that
NADK2 may play a vital role in chlorophyll synthesis and chloroplast protection
against oxidative damage [11]. Chloroplast NAD kinase
was also essential for energy transduction through the xanthophyll
cycle in photosynthesis [68]. The NADK1-deficient mutant exhibited
sensitivity to g-irradiation and paraquat-induced oxidative stress, indicating that NADK1
also has an important role in protecting plants against oxidative stress [69].
Therefore, NAD kinase of higher plants, especially CaM-regulated NAD kinase, may
provide a novel strategy for the construction of stress resistant plants or highproducing plants.
Potential Application of NAD Kinase
in the Designing of Novel Antibacterial Drug
As a crucial enzyme, the essentiality of NAD kinase has been demonstrated in several microorganisms,
such as B. subtilis [2], M.
tuberculosis [1], E. coli [3], S. enterica
[4], Streptococcus
pneumoniae [70], Staphylococcus aureus
[71], Pseudomonas
aeruginosa [36], and S. cerevisiae [7].
Differences in catalytic properties and molecular structure also exist between
microbial and human NAD kinases, such as phosphoryl donor specificity and molecular size of subunit.
In addition, exogenous oxidative stress would induce the level of NAD kinase in P. fluorescens and S. cerevisiae, but not in human, indicating that the modulation
mechanism of human NAD kinase is different from that
of microorganism [56].
As NAD kinase is an essential
enzyme in bacteria and shows significant functional diversity with its human
counterpart, it can be regarded as an attractive target for the development of
selective antibacterial drugs [15]. Several years ago, Gerdes
et
al. [72]
proposed NAD kinase as an interesting target for
novel antibacterial drugs. Raffaelli et
al. [30,31]
studied on M. tuberculosis NAD kinase, including its
catalytic property and stereo structure, and attempted to design an effective
enzyme inhibitor that could be used as a novel anti-tubercular drug for the
treatment of re-emerging tuberculosis. Bonnac et
al. [73] have
synthesized several novel analogs of NAD+, that is,
the C
Perspective
Although more studies on NAD kinases
need to be done, their important properties, physiologic functions, and
potential applications have been exhibited, which opens a wide field in the
basic and applied studies. Further studies would not only improve our
comprehension on the basic knowledge of substance metabolism, energy
metabolism, metabolic regulation, and signal transduction of living organisms,
but also provide new techniques in the development and application of antioxidative strategy, in the construction of stress
resistant plants or high-producing plants, and in the development of novel
anti-bacterial drugs.
Funding
This work was supported by a grant from the National
Natural Science Foundation of
References
1 Sassetti CM, Boyd DH and Rubin EJ. Genes
required for mycobacterial growth defined by
high-density mutagenesis. Mol Microbiol 2003, 48: 77–84.
2 Kobayashi K, Ehrlich SD, Albertini A, Amati G,
Andersen KK, Arnaud M and Asai K, et al. Essential Bacillus subtilis genes. Proc Natl Acad Sci USA 2003, 100: 4678–4683.
3 Gerdes SY, Scholle
MD, D’souza M, Bernal A, Baev MV, Farrell M and Kurnasov
OV, et al. From genetic footprinting to antimicrobial drug targets: examples in
cofactor biosynthetic pathways. J Bacteriol 2002,
184: 4555–4572.
4 Grose JH, Joss L, Velick
SF and Roth JR. Evidence that feedback inhibition of NAD kinase
controls responses to oxidative stress. Proc Natl Acad Sci USA 2006, 103: 7601–7606.
5 Cheng W and Roth JR. Evidence for two NAD kinases
in Salmonella
typhimurium. J Bacteriol 1994, 176: 4260–4268.
6 Stephan C, Renard M and Montrichard
F. Evidence for the existence of two soluble NAD+ kinase isoenzymes
in Euglena
gracilis Z. Int J Biochem
Cell Biol 2000, 32: 855–863.
7 Bieganowski P, Seidle
HF, Wojcik M and Brenner C. Synthetic lethal and
biochemical analyses of NAD and NADH kinases in Saccharomyces cerevisiae
establish
separation of cellular functions. J Biol Chem 2006, 281: 22439–22445.
8 Shi F, Kawai S, Mori S, Kono E and Murata K.
Identification of ATP-NADH kinase isozymes
and their contribution to supply of NADP(H) in Saccharomyces cerevisiae. FEBS J 2005, 272: 3337–3349.
9 Li YF and Shi F. Partial rescue of pos5 mutants by YEF1 and UTR1 genes in Saccharomyces cerevisiae. Acta
Biochim Biophys Sin 2006,
38: 293–298.
10 Turner WL, Waller JC, Vanderbeld B and Snedden WA. Cloning and characterization of two NAD kinases from Arabidopsis. Identification of a calmodulin
binding isoform. Plant Physiol
2004, 135: 1243–1255.
11 Chai MF, Chen QJ, An R, Chen YM, Chen J and
Wang XC. NADK2, an Arabidopsis chloroplastic NAD kinase, plays
a vital role in both chlorophyll synthesis and chloroplast protection. Plant
Mol Biol 2005, 59: 553–564.
12 Kawai S and Murata K. Structure and function of NAD kinase
and NADP phosphatase: key enzymes that regulate the
intracellular balance of NAD(H) and NADP(H). Biosci Biotechnol Biochem 2008, 72: 919–930.
13 Kornberg A. Enzymatic synthesis of triphosphopyridine
nucleotide. J Biol Chem
1950, 182: 805–813.
14 Kawai S, Mori S, Mukai T, Suzuki S, Hashimoto
W, Tamada T and Murata K. Inorganic
polyphosphate/ATP-NAD kinase of Micrococcus flavus and Mycobacterium tuberculosis H37Rv. Biochem
Biophys Res Commun 2000,
276, 57–63.
15 Magni G, Orsomando
G and Raffaelli N. Structural and functional
properties of NAD kinase, a key enzyme in NADP
biosynthesis. Mini Rev Med Chem 2006, 6: 739–746.
16 Murata K, Uchida T, Tani K, Kato J and 17 Garavaglia S, Galizzi
A and Rizzi M. Allosteric
regulation of Bacillus
subtilis NAD kinase by quinolinic acid. J Bacteriol
2003, 185: 4844–4850.
18 Kawai S, Fukada C, Mukai
T and Murata K. MJ19 Sakuraba H, Kawakami R and Ohshima T. First archaeal inorganic polyphosphate/ ATP-dependent NAD kinase, from hyperthermophilic archaeon Pyrococcus horikoshii: cloning, expression, and
characterization. Appl Environ Microbiol
2005, 71: 4352–4358. 20 Kawai S, Mori S, Mukai
T, Hashimoto W and Murata K. Molecular characterization of Escherichia coli NAD kinase.
Eur J Biochem 2001, 268:
4359–4365. 21 Ochiai A, Mori S,
Kawai S and Murata K. Overexpression, purification,
and characterization of ATP-NAD kinase of Sphingomonas sp. A1. Protein Expr
Purif 2004, 36: 124–130. 22
Kawai S, Mori S, Suzuki S and Murata K. Molecular cloning and identification of
UTR1 of a yeast Saccharomyces cerevisiae
as a gene
encoding an NAD kinase. FEMS Microbiol
Lett 2001, 200: 181–184. 23 Outten CE and Culotta VC. A novel
NADH kinase is the mitochondrial source of NADPH in Saccharomyces cerevisiae. EMBO J 2003, 22: 2015–2024. 24 Lerner F, Niere M, Ludwing A and Ziegler M. Structural and functional
characterization of human NAD kinase. Biochem Biophys Res Commun 2001, 288: 69–74. 25
Kornberg A, Rao NN and Ault-Riche D. Inorganic
polyphosphate: a molecule of many functions. Annu Rev
Biochem 1999, 68: 89–125. 26
Kawai S, Mori S, Mukai T, Matsukawa H, Matuo Y and Murata K. Establishment of a mass-production
system for NADP using bacterial inorganic polyphosphate/ATP-NAD kinase. J Biosci Bioeng 2001, 92: 447–452. 27
Mori S, Kawai S, Shi F, Mikami B and Murata K.
Molecular conversion of NAD kinase to NADH kinase through single amino acid residue substitution. J Biol Chem 2005, 280: 24104–24112. 28 Zerez CR, Moul DE, Gomez EG, Lopez VM and Andreoli
AJ. Negative modulation of Escherichia coli NAD kinase by NADPH
and NADH. J Bacteriol 1987, 169: 184–188. 29 Zerez CR, Moul DE and Andreoli AJ. NAD kinase from Bacillus licheniformis: inhibition by NADP and other
properties. Arch Microbiol 1986, 144: 313–316.
30 Raffaelli N, Finaurini
L, Mazzola F, Pucci L, Sorci L, Amici A and Magni G. Characterization of Mycobacterium tuberculosis
NAD kinase: functional analysis of the full-length enzyme by
site-directed mutagenesis. Biochemistry 2004, 43: 7610–7617.
31 Garavaglia S, Raffaelli
N, Finaurini L, Magni G and
Rizzi M. A novel fold revealed by Mycobacterium tuberculosis
NAD kinase, a key allosteric enzyme
in NADP biosynthesis. J Biol Chem
2004, 279: 40980–40986.
32 Bulter JR and McGuinness
ET. Candida
utilis NAD+ kinase: purification, properties and affinity gel
studies. Int J Biochem
1982, 14: 839–844.
33 Apps DK. Pigeon-liver NAD kinase. The
structural and kinetic basis of regulation of NADPH. Eur
J Biochem 1975, 55: 475–483.
34 Kawai S, Mori S and Murata K. Primary structure of inorganic
polyphosphate/ ATP-NAD kinase from Micrococcus flavus, and occurrence of substrate inorganic polyphosphate for
the enzyme. Biosci Biotechnol
Biochem 2003, 67: 1751–1760.
35 Labesse G, Douguet
D, Assairi L and Gilles AM. Diacylglyceride
kinases, sphingosine kinases and NAD kinases: distant
relatives of 6- phosphofructokinases. Trends Biochem Sci 2002, 27: 273–275.
36 Poncet-Montange G, Assairi
L, Arold S, Pochet S and Labesse G. NAD kinases use
substrate-assisted catalysis for specific recognition of NAD. J Biol Chem 2007, 282: 33925–33934.
37 Mori S, Yamasaki M, Maruyama Y, Momma K, Kawai S, Hashimoto W and Mikami B, et al. NAD-binding mode and the significance of intersubunit contact revealed by the crystal structure of Mycobacterium tuberculosis
NAD kinase-NAD complex. Biochem Biophys Res Commun 2005, 327: 500–508.
38 Oganesyan V, Huang C, 39 Liu J, Lou Y, Yokota H, 40 Foster JW and Moat AG. Nicotinamide adenine dinucleotide biosynthesis and pyridine nucleotide cycle
metabolism in microbial systems. Microbiol Rev 1980,
44: 83–105.
41 Ziegler M. New functions of a long-known molecule. Emerging roles of
NAD in cellular signaling. Eur J Biochem
2000, 267: 1550–1564.
42 Maggio-Hall LA and Escalante-Semerena JC. Alpha-5,6- dimethylbenzimidazole
adenine dinucleotide (alpha-DAD), a putative new
intermediate of coenzyme B12 biosynthesis in Salmonella typhimurium. Microbiology 2003, 149: 983–990.
43 Starai VJ, Celic I,
Cole RN, Boeke JD and Escalante-Semerena
JC. Sir2-dependent activation of acetyl-CoA synthetase by deacetylation of
active lysine. Science 2002, 298, 2390–2392.
44 Minard KI and McAlister-Henn
L. Sources of NADPH in yeast vary with carbon source. J Biol
Chem 2005, 280: 39890–39896.
45 Jo SH, Son MK, Koh HJ, Lee SM, Song IH, Kim
YO and Lee YS, et al. Control of mitochondrial redox balance and cellular defense against oxidative damage
by mitochondrial NADP+-dependent isocitrate
dehydrogenase. J Biol Chem 2001, 276: 16168–16176.
46 Pollak N, Dolle C
and Ziegler M. The power to reduce: pyridine nucleotides–small molecules with a multitude of functions. Biochem J 2007, 402, 205–218.
47 Sauer U, Canonaco F, Heri
S, Perrenoud A and Fischer E. The soluble and
membrane-bound transhydrogenases UdhA
and PntAB have divergent functions in NADPH metabolism
of Escherichia
coli. J Biol Chem 2004, 279: 6613–6619.
48 Ying W. NAD+/NADH and NADP+/NADPH in cellular functions
and cell death: regulation and biological consequences. Antioxid
Redox Signal 2008, 10: 179–206.
49 Young D, Tallman M, Landy K, Young T, Lukas
D, Lewis B and McGuinness E. Ocular lens NAD kinase: partial purification and metabolic implications. Biochem Biophys Res Commun 1998, 247: 154–158.
50 Singh R, Lemire J, Mailloux
RJ and Appanna VD. A novel strategy involved
anti-oxidative defense: the conversion of NADH into NADPH by a metabolic
network. PLoS ONE 2008, 3: e2682: 1–7.
51 Singh R, Mailloux RJ, Puiseux-Dao
S and Appanna VD. Oxidative stress evokes a metabolic
adaptation that favors increased NADPH synthesis and decreased NADH production
in Pseudomonas
fluorescens. J Bacteriol 2007, 189: 6665–6675.
52 Lemire J, Kumar P, Mailloux
RJ, Cossar K and Appanna
VD. Metabolic adaptation and oxaloacetate homeostasis
in P. fluorescens exposed to aluminum toxicity. J Basic Microbiol
2008, 48: 252–259.
53 Fukuda C, Kawai S and Murata K. NADP(H) phosphatase
activities of archaeal inositol
monophosphatase and eubacterial
3′-phosphoadenosine 5′-phosphate phosphatase. Appl Environ Microbiol 2007, 73:
5447–5452.
54 De Felipe FL, Kleerebezem M, De Vos WM and Hugenholtz J. Cofactor
engineering: a novel approach to metabolic engineering in Lactococcus lactis
by
controlled expression of NADH oxidase. J Bacteriol 1998, 180: 3804–3808.
55 Strand MK, Stuart GR, Longley MJ, Graziewicz
MA, Dominick OC and Copeland WC. POS5 gene of Saccharomyces cerevisiae
encodes a
mitochondrial NADH kinase required for stability of
mitochondrial DNA. Eukaryot Cell 2003, 2: 809–820.
56 Pollak N, Niere M
and Ziegler M. NAD kinase levels control the NADPH
concentration in human cells. J Biol Chem 2007, 282: 33562–33571.
57 Akella SS and Harris C. Developmental
ontogeny of NAD kinase in the rat conceptus.
Toxicol Appl Pharmacol 2001, 170: 124–129.
58 Outten CE and Culotta
VC. Alternative start sites in the Saccharomyces cerevisiae
GLR1 gene are
responsible for mitochondrial and cytosolic isoforms of glutathione reductase.
J Biol Chem 2004, 279: 7785–7791.
59 Imlay JA and Linn S. Toxic DNA damage by hydrogen peroxide through
Fenton reaction in vivo and in vitro. Science 1988, 240: 640–642.
60 Tuttle SW, Maity A, Oprysko
PR, Kachur AV, Ayene IS, Biaglow JE and Koch CJ. Detection of reactive oxygen
species via endogenous oxidative pentose phosphate cycle activity in response
to oxygen concentration: implications for the mechanism of HIF-1alpha
stabilization under moderate hypoxia. J Biol Chem 2007, 282: 36790–36796.
61 Epel D, Patton C, Wallace RW and Cheung WY. Calmodulin activates NAD kinase of
sea urchin eggs: an early event of fertilization. Cell 1981, 23: 543–549.
62 Williams MB and Jones HP. Calmodulin-dependent
NAD kinase of human neutrophils.
Arch Biochem Biophys 1985,
237: 80–87.
63 Means AR, VanBerkum MFA, Bagchi
I, Lu KP and Rasmussen CD. Regulatory functions of calmodulin.
Pharmacol Ther 1991, 50,
255–270.
64 Lee SH, Seo HY, Kim JC, Heo
WD, Chung WS, Lee KJ and Kim MC, et al. Differential activation of NAD kinase by plant calmodulin isoforms. J Biol Chem 1997, 272: 9252–9259.
65 Harding SA, Oh SH and Roberts DM. Transgenic tobacco expressing a
foreign calmodulin gene shows an enhanced production
of active oxygen species. EMBO J 1997, 16: 1137–1144.
66 Hayashi M, Takahashi H, Tamura K, Huang J, Yu LH, Kawai-Yamada M and Tezuka T, et al. Enhanced dihydroflavonol-4-reductase
activity and NAD homeostasis leading to cell death tolerance in transgenic
rice. Proc Natl Acad Sci USA 2005, 102: 7020–7025.
67 Ruiz JM, Sa′nchez E, Garc齛′ PC, Lo′pez-Lefebre LR, Rivero RM and Romero L. Proline
metabolism and NAD kinase activity in green bean
plants subjected to cold-shock. Phytochemistry 2002,
59: 473–478.
68 Takahashi H, Watanabe A, Tanaka A, Hashida
SN, Kawai-Yamada M, Sonoike K and Uchimiya
H. Chloroplast NAD kinase is essential for energy
transduction through the xanthophyll cycle in
photosynthesis. Plant Cell Physiol 2006, 47: 1678–1682.
69 Berrin JG, Pierrugues
O, Brutesco C, Alonso B, Montillet
JL, Roby D and Kazmaier M. Stress induces the
expression of AtNADK-1, a gene encoding a NAD(H) kinase
in Arabidopsis
thaliana. Mol
Genet Genomics 2005, 273: 10–19.
70 Thanassi JA, Hartman-Neumann SL, Dougherty
TJ, Dougherty BA and Pucci MJ. Identification of 113
conserved essential genes using a highthroughput gene
disruption system in Streptococcus pneumoniae. Nucleic Acids Res 2002, 30:
3152–3162.
71 Zalacain M, Biswas
S, Ingraham KA, Ambrad J,
Bryant A, Chalker AF and Iordanescu
S, et al. A global approach to identify
novel broadspectrum antibacterial targets among
proteins of unknown function. J Mol Microbiol Biotechnol 2003, 6: 109–126.
72 Gerdes SY, Scholle
MD, D’souza M, Bernal A, Baev MV, Farrell M and Kurnasov
OV, et al. From genetic footprinting to antimicrobial drug targets: examples in
cofactor biosynthetic pathways. J Bacteriol 2002,
184: 4555–4572.
73 Bonnac L, Chen LQ, Pathak
R, Gao GY, Ming Q, Bennett E and Felczak
K, et al. Probing binding requirements
of NAD kinase with modified substrate (NAD)
analogues. Bioorg Med Chem Lett 2007, 17: 1512–1515.
|
Acta Biochimica et Biophysica Sinica