![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Department of Nutrition, University of California, Davis, Davis, CA 95616
2To whom correspondence should be addressed.
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONPQQTTQ and the copper-complexed...TPQ and lysyl tyrosine...CONCLUSIONREFERENCES |
|---|
KEY WORDS: • pyrroloquinoline quinone • topaquinone • tryptophan tryptophylquinone • lysine tyrosylquinone • quinoproteins
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONPQQTTQ and the copper-complexed...TPQ and lysyl tyrosine...CONCLUSIONREFERENCES |
|---|
). Pyrroloquinoline quinone
(PQQ)3
was the first of the ortho-(O)-quinone cofactors to be identified
(Salisbury et al. 1979
). In many prokaryotic organisms,
PQQ serves as a noncovalent cofactor for various simple sugar and
alcohol dehydrogenases (Goodwin and Anthony 1998
).
Following the discovery of PQQ, (Fig. 1
), subsequent
observations led to the identification of other cofactors in the
o-quinone cofactor family, e.g., tryptophan
tryptophylquinone (TTQ), trihydroxyphenylalanyl quinone (topaquinone or
TPQ), lysine tyrosylquinone (LTQ) and the copper-complexed
cysteinyltyrosyl radical. In contrast to PQQ, these cofactors are
covalently linked to the enzymes that they serve (Fig. 2
).
|
|
In the second part of this review, functional relationships involving TPQ and LPQ will be described. It is now well established that TPQ and LTQ are found at the active sites of copper-containing amine oxidases, such as diamine oxidase (TPQ) and lysyl oxidase (LTQ). The formation and activity of TPQ- and LTQ-requiring enzymes are dependent on dietary copper intake. Mention will also be made of TTQ and the copper-complexed cysteinyltyrosyl radical, although these cofactors appear to be utilized primarily in bacterial and fungal quinoenzymes.
|
PQQ |
|---|
|
TOPABSTRACTINTRODUCTIONPQQTTQ and the copper-complexed...TPQ and lysyl tyrosine...CONCLUSIONREFERENCES |
|---|
PQQ, (4,5-dihydro-4,
5-dioxo-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid) or
methoxatin, as it is designated in earlier literature, is highly
soluble, heat-stable and capable of continuous redox cycling (Fig. 1)
. In the presence of amino acids, PQQ readily forms numerous
imidazole derivatives and, with time, oxazole adducts (Mitchell et al. 1999
).
The chemical properties of PQQ are analogous to combining some of
the best chemical features of ascorbic acid (reducing potential),
riboflavin (redox reactions), and pyridoxal (PL) (carbonyl reactivity)
cofactors into one molecule. PQQ has the ability to carry out redox
cycling so that picomole amounts of PQQ are capable of generating
micromolar amounts of product (Fluckiger et al. 1993
,
1995
). On a molar basis, PQQ is at least 100 times more
efficient than ascorbic acid, menadione and all of the isoflavinoids
and polyphenolic compounds tested to date in assays that assess redox
cycling potential (Fig. 3
).
|
). For example, PQQ is a high-affinity substrate
for erythrocyte flavin reductase. For bovine erythrocyte flavin
reductase, the apparent Km for PQQ is 2
µmol/L, which is less than the values observed for riboflavin, FMN,
or FAD, e.g., ~10–25 µmol/L (Hultquist et al. 1993
). The pyrroloquinoline quinol generated by this reaction
also interacts rapidly with ferryl myoglobin radical and can protect
isolated rabbit heart preparations from re-oxygenation injury
(Xu et al. 1993
).
PQQ catalyzes the continuous oxidation of primary amines. For example,
PQQ can carry out the oxidation of pyridoxamine 5'-phosphate to PL
5'-phosphate at rates that even exceed those of pyridoxamine
5'-phosphate oxidase (Churchich 1989
). PQQ also
catalyzes the nonspecific oxidation of peptidyl lysine in elastin and
collagen substrates (Shah et al. 1992
). The optimal rate
of elastin oxidation occurs at a 2:1 PQQ/Cu+2 ratio.
Elastin oxidation under aerobic conditions results in the formation of
aldehydes and eventually interchain crosslinks.
Prokaryotic production and utilization of PQQ.
Numerous bacteria including methylotrophic bacteria,
Pseudomona, Acetobacter and
Gluconobacter species are capable of PQQ synthesis
(Duine et al. 1990
). Currently, the best evidence
indicates that PQQ is derived from an annulation between glutamyl (or
glutaminyl) and tyrosyl residues (Houck et al. 1988
).
Although the pathway for PQQ synthesis remains to be resolved, all of
the requisite genes for PQQ synthesis have been cloned.
Acinetobacter calcoaceticus requires at least four genes for
PQQ synthesis (Goosen et al. 1989
), whereas seven genes
are required in Methylobacterium extorquens (Morris et al. 1994
). In A. calcoaceticus, three of the four
genes encode proteins of molecular weights of 29,700, 10,800 and 43,600
Da. The fourth gene encodes a polypeptide of only 24 amino acids. In
the absence or modification of this gene, optimal PQQ synthesis does
not occur. Moreover, the small peptide is relatively conserved,
although size of the peptide varies depending upon the organism. The
peptide is 23 amino acids in Klebsiella pneumoniae
(Meulenberg et al. 1992
), 29 amino acids in
Methylobacterium extorquens (Morris et al. 1994
), 24 amino acids in Methylobacillus flagellatum
(Gomelsky et al. 1996
) and 24 or 39 amino acids in
Pseudomonas fluorescens (Schnider et al. 1995
). The site of synthesis is thought to involve a conserved
glu-X-X-X-tyr motif in the small peptide. In A.
calcoaceticus, when glutamate is replaced by aspartate or tyrosine
is replaced by phenylalanine, PQQ is not synthesized (Goosen et al. 1992
). In K. pneumoniae a shift in the reading
frame of the small peptide also abolishes PQQ synthesis
(Meulenberg et al. 1992
). These observations imply that
the peptide serves as a complex substrate for PQQ synthesis. However, a
recent study by Toyama and Lidstrom (1998)
suggests that an alternative
path for PQQ synthesis may exist in M. extorquens. In
mutants lacking the gene for the small peptide, PQQ is synthesized, but
at a reduced rate, i.e., 10–20% of that for the corresponding
M. extorquens wild type.
It is interesting to note that there are bacterial organisms that do
not make PQQ even though they contain proteins that require PQQ as a
cofactor. In the closely related enteric bacterial family, K.
pneumoniae, Escherichia coli and Salmonella
typhimurium, all synthesize a PQQ-dependent enzyme glucose
dehydrogenase (GDH), but only K. pneumoniae synthesizes an
active holo-GDH enzyme (Matsushita et al. 1997
).
E. coli and S. typhimurium are not capable of PQQ
synthesis, but are capable of utilizing PQQ as a "vitamin" under
certain nutrient-limiting conditions. The apo-GDH from E.
coli, S. typhimurium and similar organisms becomes
functional (holo-GDH) when PQQ is added. The reconstitution of GDH and
other PQQ requiring enzymes with PQQ has become the basis for sensitive
enzyme assays for PQQ quantitation (van der Meer et al. 1990
). E.
coli mutants that are dysfunctional in glucokinase and
phosphotransferase are able to grow similarly to wild type when
supplemented with PQQ (Adamowicz et al. 1991
). In
addition, PQQ is a chemotactic attractant in E. coli
organisms (Dejonge et al. 1996
). By using PQQ, E.
coli retains an alternate glucose-metabolizing pathway, which
could provide selective advantage, particularly in aerobic- and
phosphate-limiting environments (Fliege et al. 1992
).
PQQ in foods.
In addition to bacteria and fermented products, PQQ has been detected
in animal and plant tissues (Bishop et al. 1994
,
Kumazawa et al. 1995
, Mitchell et al. 1999
). Several approaches for detection and quantitation of PQQ
have been described. However, problems associated with specificity or
exclusion of PQQ-like compounds have led to both over- and
underestimation of PQQ and PQQ-like compounds. For example, the
methods based on redox cycling are sensitive (Fig. 3)
, but may
overestimate PQQ concentrations owing to lack of specificity
(Fluckiger et al. 1995
, Paz et al. 1996
).
Other methods based on enzymatic (Geiger and Gorisch 1987
, Olsthoorn and Duine 1996
), immunologic
(Marini et al. 1993
, Narita and Morishita 1995
), or chemical derivation and chromatographic separation
(Bergethon 1990
, Buffoni et al. 1992
,
Esaka et al. 1993
, Kano et al. 1991
,
Kumazawa et al. 1992
, 1995
, Zhang et al. 1995
) are more specific, but often exclude PQQ
derivatives. These methods therefore may underestimate the total
amounts of PQQ and PQQ derivatives.
PQQ easily forms imidazole derivatives in the presence of amino acids.
Owing to the high reactivity of PQQ and the complex nature of tissues
and biological fluids, PQQ most likely exists in foods as either
imidazole or oxazole adducts. Mitchell et al. (1999)
determined that
human milk contains 140–180 ng/mL of PQQ and IPQ of which ~ 80–90% is present as IPQ. On a dry weight basis, this amounts to 1–2
µg of PQQ/g of solid, which is also similar to the PQQ concentrations
reported for bovine milk (Fluckiger et al. 1993
).
Table 1
contains concentrations of PQQ and selected vitamins in foods. The
reported values for PQQ in the table were from studies in which
chromatographic separation and validation of PQQ and PQQ-like
compounds were achieved by either chemical derivation or by mass
spectrometry. PQQ is present at the same order of magnitude as biotin
and 5–10% of values typically reported for folic acid. It is also
important to note that PQQ appears readily absorbed. Smidt et al. (1991a)
determined that the apparent absorption of an oral dose of
14C-PQQ (80 nmol or ~30 µg) ranges from 20 to
80%. The 14C-PQQ was administered to adult mice
in the fed state. The percentages were estimated from the amount of
radioactivity present in urine and tissues at 24 h after
administration.
|
Although the function of PQQ in animals remains unclear, the ability to
carry out continuous redox cycling suggests a role for PQQ as a
cofactor or antioxidant. Mice fed chemically defined diets devoid of
PQQ that are otherwise nutritionally adequate have impaired neonatal
growth and abnormal features. Maximal growth is achieved when as little
as 1 nmol or 300 ng of PQQ is added per g of diet or per 4–5 kcal
(16–17 KJ) (Steinberg et al. 1994
). Signs of PQQ
deprivation include friable skin, evidence of hemorrhage and
diverticuli, reduction in general fitness, and a hunched posture.
Decreased fertility (fewer successful pregnancies and smaller litter
size) and defects in immune function (reduction in interleukin-2 levels
and loss of sensitivity of B- and T-cells to mitogens) also occurs
with PQQ deficiency (Steinberg et al. 1994
).
Further, the number and size of mitochondria are affected by PQQ
deficiency. PQQ-deficient mice have a 30–40% reduction in the numbers
of mitochondria compared to supplemented mice. The mitochondrial area
per cell is also reduced (~30%) in PQQ-deficient mice compared to
corresponding supplemented mice. Further, mitochondrial preparations
from PQQ-deficient mice respond poorly in assays designed to assess
the respiratory control (Stites et al. 1996
). For
example, the values for the respiratory control rate and P/O ratio are
observed to be within normal ranges for PQQ-supplemented and
-deficient mice. However, less than half of the mitochondrial
preparations from PQQ-deficient mice remained viable or patent in
assays, whereas all of the preparations from PQQ-supplemented mice
could be used.
The response to PQQ supplementation is most obvious in neonates
(F1 generation) derived from PQQ-deprived
dams (F0 generation). However, at the onset of
sexual maturation (6–8 wk), F1 generation mice
fed PQQ-deficient diets exhibit "catch-up" growth
(Steinberg et al. 1994
). At this time, PQQ is detected
in fecal samples. Note that studies by Smidt et al. (1991b)
suggest
that PQQ is not synthesized by microorganisms common to the mouse
intestinal tract. This suggests that PQQ may be synthesized
sufficiently at the onset of sexual maturation or is only of utility to
the neonate. Work in several laboratories is currently attempting to
resolve this issue.
In cell culture experiments, PQQ and IPQ enhance cell growth and
proliferation (Naito et al. 1993
). PQQ and IPQ enhance
the incorporation of [3H]-thymidine into human
fibroblast cells. PQQ causes stimulation at concentrations as low as 3
nmol/L, whereas IPQ causes stimulation at ~15 nmol/L IPQ. What is
remarkable about these observations, both in vivo and in vitro, are the
concentrations at which PQQ produces effects, i.e., nmol PQQ/g of diet
or nmol/L of cell culture medium. Such concentrations are usually
characteristic of potent cytokines and related growth factors.
Antioxidant properties.
At concentrations of 15–30 µmol/kg body weight, PQQ and IPQ function
as antioxidants. Tsuchida et al. (1993)
and Urakami et al. (1997)
have
reported that PQQ and IPQ protect mice against acute liver damage,
induced by agents, such as CCl4. PQQ treatment
also decreases glucocorticoid (hydrocortisone)- induced cataract
formation in fertilized chicken eggs (Nishigori et al. 1989
, 1993
, Urakami et al. 1997
).
A possible mechanism for the decrease in cataract formation is
restoration of glutathione levels, which are reduced in response to
hydrocortisone.
As additional examples, using a carrageenin model to produce
inflammation and paw edema in rats, Hamagishi et al. 1990 observed that
PQQ administered (i.p.) at 10 or 30 mg PQQ/kg body weight caused a
decrease in carrageenin-induced edema by 39 and 76%, respectively.
Both PQQ and IPQ decreased CCl4-enhanced
chemiluminescence in isolated hepatocytes (Urakami et al. 1997
). It is also noteworthy that PQQ is a better inhibitor of
chemiluminescence (initiated by zymosan, carrageenin or
N-formyl-methionyl-leucyl-phenylalanine) in mouse peritoneal
cells than 
-tocopherol and ascorbic acid (Hamagishi et al. 1990
). On a molar basis, PQQ was fifteen times more effective
than ascorbic acid in decreasing chemiluminescence generated by the
xanthine-xanthine oxidase reaction and seven times more effective
than -tocopherol at preventing lipid peroxidation in rat brain
preparations (Hamagishi et al. 1990
).
PQQ toxicity.
It is important to point out that compounds that engage in redox
cycling can also be effective free radical initiators. Although
toxicity studies are limited, nephrotoxicity and oxidative damage have
been reported when 35 µmol or more per kg body weight (~10 mg
PQQ/kg) was administered daily by injections (i.p) to rats over a
4–5-d period (Watanabe et al. 1989
). PQQ has also been
demonstrated to initiate DNA damage in vitro (Hiraku and Kawanishi 1996
). However, relatively high concentrations of PQQ
(2 µmol/L) are required for DNA damage relative to the concentrations
of PQQ needed to cause cell proliferation (nmol/L amounts; Naito et al. 1993
). In addition, an electron regeneration system is needed to
initiate DNA damage. For example, an
NADH/Cu2+/PQQ-dependent redox system is very
efficient in generating superoxide and hydrogen peroxide. Interestingly
DNA cleavage does not occur when Fe2+,
Fe3+ or Mn2+ is substituted
for Cu2+.
PQQ and neural cells and tissue.
Nerve cells become excited upon stimulation of NMDA
glutamate-receptors. In cell culture experiments, PQQ protects
neuronal cells from NMDA toxicity by directly oxidizing the receptor’s
NMDA redox site (Aizenman et al. 1992
,
1994
; Scanlon et al. 1997
). Jensen et al. (1994)
have extended these observations by showing in vivo that PQQ
protects against the likelihood of severe stroke in an experimental
animal model for stroke and brain hypoxia. PQQ administration reduced
the infarct size when the animals were pretreated with PQQ prior to
induction of hypoxia and ischemia.
PQQ also increases production of nerve growth factor (NGF) in some cell lines. NGF is required for peripheral sympathetic and sensory neuron function and aids in protecting the magnocellular cholinergic neurons in the basal forebrain nuclei. These areas are involved in memory and learning and are often significantly damaged in Alzheimer’s disease.
In L-M cells (a nerve growth factor-productive cell
line), PQQ enhances NGF synthesis 50-fold and PQQ-TME increases NGF
synthesis 70-fold. However, IPQ-TME has no NGF-enhancing
effects (Urakami et al. 1996, Yamaguchi et al. 1993
). PQQ also enhances NGF synthesis and secretion in mouse
astroglial cells (17-fold) and human WS-1 cells (6-fold), but has no
effect in mouse BALB c/3T3 cells (Murase et al. 1993
).
The mechanism for enhancement is currently under investigation.
Features of this response have also been observed in vivo. Yamaguchi et al. (1993)
have reported that PQQ in the form of the trimethyl ester
imidazole derivative (IPQ-TME) causes a nearly 2-fold increase in NGF
in the neocortex of rat brain.
It is of interest to note that TOPA in the form of 6-hydroxy-dopa or
TPQ acts as a potent neurotoxin. TPQ interacts with NMDA glutamatergic
receptors and produces neuronal death in contrast to the neurotrophic
effects of PQQ (Newcomer et al. 1995
). Using a
pheochromocytoma catecholaminergic cell line, (Newcomer et al. 1995
) have identified TOPA-related products. DOPA secretion
from pheochromocytoma cells coincides with detectable generation of
TOPA-related compounds. Inhibition of TOPA formation occurs upon
addition of GSH. This suggests that TOPA and related products probably
occur by the extracellular auto-oxidation of DOPA, i.e., TOPA and
TPQ are selective non-NMDA agonists that can be synthesized by
brain tissue.
GSH decreases the neurotoxicity of TOPA or TPQ through the formation of
glutathionyl complexes. These complexes switch the pathway away from
the formation of toxic factors to less toxic pheomelanins (Nappi and Vass 1994
). In the absence of GSH, TPQ is a component of
catecholamine toxicity that is generally underestimated
(Newcomer et al. 1995
). As noted above, the toxic
effects of TPQ and TOPA are in marked contrast to the protective
interactions of PQQ with NMDA receptors.
|
TTQ and the copper-complexed cysteinyltyrosyl radical |
|---|
|
TOPABSTRACTINTRODUCTIONPQQTTQ and the copper-complexed...TPQ and lysyl tyrosine...CONCLUSIONREFERENCES |
|---|
has
provided a recent review describing the role of both cofactors. The
copper-complexed cysteinyltyrosyl radical is found in fungal
galactose oxidase (Baron et al. 1994
). TTQ is a cofactor
for methylamine dehydrogenase and aromatic amine dehydrogenase.
The activation of galactose oxidase by copper is novel, because of
catalysis of a protein-derived radical as an active site cofactor,
i.e., a cysteinyltyrosyl radical (Baron et al. 1994
).
The activation of certain bacterial amine oxidases is novel because of
the use of TTQ as a cofactor. McIntire and his colleagues studying
methylamine dehydrogenase provided the first unequivocal proof that TTQ
was the redox prosthetic group in an alkylamine dehydrogenase.
Methylamine redox reactions involve methylamine dehydrogenase (MADH),
the type I copper protein amicyanin and cytochrome C. MADH is commonly
found in methylotrophic soil bacteria. Bishop et al. (1998)
recently
isolated an aromatic amine dehydrogenase that contains TTQ, which
broadens the specificity of TTQ-containing dehydrogenases to
include both alkyl and aromatic amines.
|
TPQ and lysyl tyrosine quinone |
|---|
|
TOPABSTRACTINTRODUCTIONPQQTTQ and the copper-complexed...TPQ and lysyl tyrosine...CONCLUSIONREFERENCES |
|---|
TPQ is the principal cofactor in copper containing amine oxidases.
Copper aids in initiating the oxidation of a tyrosyl residue to form
TPQ (Cai et al. 1997
). TPQ is derived from peptidyl
tyrosine in the sequence, -Asn-X-Glu-, where X
represents the modified tyrosine. The tyrosyl residue is first
converted to peptidyl dopa and then to TPQ. The unsaturated quinone
structure of dopaquinone promotes the reaction at the C-2 position to
produce TPQ (Fig. 4
). Recent evidence suggests that copper is required for the initiation
of the reaction at the C-2 position.
|
 |
The classical example of an amine oxidase enzyme is benzylamine or
polyamine oxidase, which was first fully characterized from bovine
plasma (McIntire 1998
and references cited). Lysyl
oxidase and histaminase are other important examples. Generally, such
enzymes are semicarbazide-sensitive and when reacted with
hydrazines, e.g., p-nitrophenyl hydrazine, form covalent
complexes with the cofactor TPQ. Another common feature is a catalytic
base at the active site, usually an aspartic acid residue (Hevel et al. 1999
).
Amine oxidases carry out reactions in two steps in the manner of a
so-called ping-pong reaction (Shah et al. 1993
). The
first part of the reaction initiates reduction of the cofactor, and in
the second phase an oxidation occurs.
|
| (1) |
In the scheme above, E represents
the o-quinone form of TPQ and F represents the
aminoquinol formed from the half reaction (also see Fig. 5
).
|
-amine function of
lysyl residues in a variety of proteins may be oxidatively deaminated.
From a functional perspective, more information is known about lysyl
oxidase than other amine oxidases. Lysyl oxidase serves as a key enzyme
in the growth and development of all higher animals (Rucker et al. 1998
). Both intracellular and extracellular forms of the
enzyme exist. In malignant cells, it is currently speculated that the
intracellular form(s) of lysyl oxidase target as substrates oncogenic
and growth-promoting transcription factors. Two examples are RAS
oncogene and IRF-1 transcription factor (Kenyon et al. 1993
, Ren et al. 1998
, Tan et al.
1996). Within the extracellular matrix (ECM), lysyl oxidase
catalyzes the crosslinking of the collagens or elastin.
Developmental processes beyond gastrulation are blocked when lysyl
oxidase is inhibited. (Rucker et al. 1998
and references
cited). In addition, at least one form of lysyl oxidase localizes in
the nucleus (Li et al. 1997
).
The cofactor for lysyl oxidase is LTQ. The formation of LTQ requires an
additional step (Fig. 5)
, resulting in the formation of the lysyl
adduct of TPQ (Wang et al. 1997
). This cofactor was
identified following derivation of lysyl oxidase with
p-nitrophenylhydrazine followed by treatment with
thermolysin and finally separation of the resulting peptides. Edman
degradation of the protein indicates that the quinone-containing
peptide is crosslinked with another peptide. Extensive mass spectral
analysis and Raman spectroscopy eventually led to the identification of
LTQ. LTQ exists as a neutral 79-quinone, due to the nitrogen associated
with lysine. In contrast, TPQ exists as a resonance-stabilized
hybrid with a net negative charge (Wang et al. 1997
).
Role of copper in TPQ formation.
Copper has two functions: the single-turnover and modification of
peptidyl tyrosine to form TPQ, and the subsequent involvement in the
oxidative deamination of the primary amine substrates. Copper-catalyzed
generation of TPQ is based on observations by (Cai et al. 1997
, Matsuzaki et al. 1994
, Rinaldi et al. 1998
, Ruggiero and Dooley, 1999
,
Ruggiero et al. 1997
, Wang et al. 1997
).
The reaction involves a six-electron oxidation of tyrosine to form
TPQ in which 2 mol of O2 are consumed in the
reaction and one mole of
H2O2 is produced
(Ruggiero and Dooley 1999
). Copper must first be
incorporated into the enzymes active center and then TPQ is formed
(Fig. 4)
. In related studies, Mure and Tanizawa (1997)
have utilized
4-tertiary-butyl-derived compounds to study TPQ generation. The
researchers examined the effects of Cu+2 and
Zn+2 additions. They concluded that the role of
the active site copper ion in TPQ biogenesis is limited to the
catalysis of the two quinolation steps. Interestingly, the activity of
a fully processed copper-depleted enzyme can be regenerated with
the addition of cobalt. Further, activation by cobalt has mechanistic
implications. A semiquinone radical is not formed as an intermediate in
the enzymatic reaction, e.g., an oxidative deamination
(Agostinelli et al. 1998
).
As an additional mechanistic feature of TPQ formation, Nakamura et al. (1996)
have observed (based on changes in Raman spectra) that when
apo-enzyme is reacted with Cu+2 in the
presence of H218O, the oxygen at
the C-2 position of TPQ most likely comes from the solvent and not
O2. Due to the electron destabilization between
the oxygen atoms associated with C-2 and C-4, the oxygen at the C-5
position has the predominant carbonyl character (Nakamura et al. 1996
).
LTQ formation and dietary copper.
A relationship between the expression of amine and lysyl oxidase
activity and copper intake has been established since the 1960s. For
example, intakes of copper over the range of 0.5 to 16 µg copper/g of
diet causes a progressive increase in lysyl oxidase activity in tendon
and bone (Rucker et al. 1999
). These observations, in
addition to a number of early observations, are the basis for using
amine and lysyl oxidase activities for assessment of dietary copper
(Rucker et al. 1998
). The relationship between copper
intake and lysyl oxidase activity appears to be due to enzyme
activation and not to changes in lysyl oxidase mRNA or content within
the extracellular matrix (Rucker et al. 1998
).
What are the processes that link lysyl tyrosine quinone formation to
copper intake and eventually lysyl oxidase activation? For lysyl
oxidase, some clues come from the recognition that two genetic
diseases, Menkes disease and occipital horn syndrome (possibly a form
of X-linked cutis laxa), are related to defects in Cu-ATPase
genes, specifically P-ATPase-7A, the gene that is involved in copper
transport. Cellular copper homeostasis appears to be regulated mostly
by cellular copper efflux pathways. Cu-ATPase activity is an
important component of the copper efflux pathway. An excellent recent
review on this topic has been provided by (Pena et al. 1999
).
The exit of copper from connective tissue cells occurs by transport
involving secretory vesicles with the eventual release of copper into
extracellular space. Lysyl oxidase obviously interacts with copper at
some point during the egress pathways designed to transport either
copper or lysyl oxidase out of cells. More detailed examination of this
process should eventually lead to an explanation as to why there is
such remarkable linkage between lysyl oxidase activation, vesicular
copper concentration and dietary copper intake (Fig. 6
).
|
|
CONCLUSION |
|---|
|
TOPABSTRACTINTRODUCTIONPQQTTQ and the copper-complexed...TPQ and lysyl tyrosine...CONCLUSIONREFERENCES |
|---|
TPQ and LPQ are not required as nutrients, but their formation is dependent on dietary copper intake. In this regard, it may be inferred that TPQ- and LPQ-containing enzymes may be indicators of copper status.
Further studies that focus on the action of these quinone compounds should have broad impact. Specifically, mechanistic studies that aid in defining the function of PQQ in higher animals could provide a more solid basis for explaining the general systemic effects of other quinone compounds including numerous flavinoids and flavinols that are common in diets.
|
ACKNOWLEDGMENTS |
|---|
-carboxyglutamic acid. There are many who miss his advice, humor and
enthusiastic support. |
FOOTNOTES |
|---|
3 Abbreviations used: ECM, extracellular matrix; GDH, glucose dehydrogenase; GSH, glutathione; IPQ,
imidazolopyrroloquinoline quinone; LTQ, lysine tyrosylquinone; NGF, nerve growth factor; NMDA,
N-methyl-D-aspartic acid; PAQ, phenantrene quinone; PL, pyridoxal; PQQ, pyrroloquinoline quinone; TME, trimethyl
ester; TOPA, trihydroxyphenylalanine; TPQ, topaquinone; TTQ, tryptophan tryptophylquinone.
Manuscript received October 4, 1999. Initial review completed November 2, 1999. Revision accepted December 6, 1999.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONPQQTTQ and the copper-complexed...TPQ and lysyl tyrosine...CONCLUSIONREFERENCES |
|---|
1.
Adamowicz M., Conway T., Nickerson K. W. Nutritional complementation of oxidative glucose metabolism in Escherichia coli via pyrroloquinoline quinone-dependent glucose dehydrogenase and the Entner-Doudoroff pathway. Appl. Environ. Microbiol. 1991;57:2012-2015
2. Aizenman E., Boeckman F. A., Rosenberg P. A. Glutathione prevents 2,4,5-trihydroxyphenylalanine excitotoxicity by maintaining it in a reduced, non-active form. Neurosci. Lett. 1992;144:233-236[Medline]
3. Aizenman E., Jensen F. E., Gallop P. M., Rosenberg P. A., Tang L. H. Further evidence that pyrroloquinoline quinone interacts with the N-methyl-D-aspartate receptor redox site in rat cortical neurons in vitro. Neurosci. Lett. 1994;168:189-192[Medline]
4. Agostinelli E., De Matteis G., Mondovi B., Morpurgo L. Reconstitution of Cu2+-depleted bovine serum amine oxidase with Co2+. Biochemical J 1998;330:383-387
5.
Baron A. J., Stevens C., Wilmot C., Seneviratne K. D., Blakeley V., Dooley D. M., Phillips S. E., Knowles P. F., McPherson M. J. Structure and mechanism of galactose oxidase. The free radical site. J. Biol. Chem. 1994;269:25095-25105
6. Bergethon P. R. Amperometric electrochemical detection of pyrroloquinoline quinone in high-performance liquid chromatography [published erratum appears in Anal. Biochem. 1991 May 1;194(2):449]. Anal. Biochem. 1990;186:324-327[Medline]
7. Bishop A., Paz M. A., Gallop P. M., Karnovsky M. L. Methoxatin (PQQ) in guinea-pig neutrophils. Free Radic. Biol. Med. 1994;17:311-320[Medline]
8. Bishop G. R., Zhu Z., Whitehead T. L., Hicks R. P., and Davidson V. L. Identification of reaction products and intermediates of aromatic-amine dehydrogenase by 15N and13C NMR. Biochemical J 1998;330:1159-1163
9. Buffoni F., Cambi S., Moneti G. Pyrroloquinoline quinone, a method for its isolation and identification by mass spectrometry. Biochim. Biophys Acta 1992;1116:297-304[Medline]
10. Cai D., Williams N. K., Klinman J. P. Effect of metal on 2,4,5-trihydroxyphenylalanine (topa) quinone biogenesis in the Hansenula polymorpha copper amine oxidase. J. Biolog. Chem. 1997;272:19277-19281
11. Churchich J. E. Reaction of pyridoxamine-5-P with pyrroloquinoline quinone (coenzyme PQQ). Biofactors 1989;2:113-116[Medline]
12.
Dejonge R., Demattos M. J. T., Stock J. B., Neijssel O. M., Stock J. B., Neijssel O. M. Pyrroloquinoline quinone, a chemotactic attractant for Escherichia coli. J. Bacteriol. 1996;178:1224-1226
13. Duine J. A., van der Meer R. A., Groen B. W. The cofactor pyrroloquinoline quinone. Annu. Rev. Nutr. 1990;:297-318
14. Esaka Y., Yamaguchi Y., Kano K., Goto M. Separation of amino acid-oxazole derivatives of the redox coenzyme pyrroloquinoline quinone by capillary zone electrophoresis. J. Chromatogr. A. 1993;652:225-232[Medline]
15.
Fliege R., Tong S., Shibata A., Nickerson K. W., Conway T. The Entner-Doudoroff pathway in Escherichia coli is induced for oxidative glucose metabolism via pyrroloquinoline quinone-dependent glucose dehydrogenase. Appl. Environ. Microbiol. 1992;58:3826-3829
16. Fluckiger R., Paz M. A., Gallop P. M. Redox-cycling detection of dialyzable pyrroloquinoline quinone and quinoproteins. Meth. Enzymol. 1995;258:140-149[Medline]
17. Fluckiger R., Paz M., Hensen E., Gallop P. M. Glycine-dependent redox cycling and other methods for PQQ and quinoprotein detection. Davidson V. L. eds. Principles and Applications of Quinoproteins 1993:331-340 Marcel Dekker Inc. New York, NY.
18. Geiger O., Gorisch H. Enzymatic determination of pyrroloquinoline quinone using crude membranes from Escherichia coli. Anal. Biochem. 1987;164:418-423[Medline]
19. Gomelsky M., Biville F., Gasser F., Tsygankov Y. D. Identification and characterization of the pqqDGC gene cluster involved in pyrroloquinoline quinone production in an obligate methylotroph Methylobacillus flagellatum. FEMS Microbiol. Lett. 1996;141:169-176[Medline]
20. Goodwin P. M., Anthony C. The biochemistry, physiology and genetics of PQQ and PQQ-containing enzymes. Adv. Microb. Physiol. 1998;40:1-80[Medline]
21.
Goosen N., Horsman H. P., Huinen R. G., van de Putte P. Acinetobacter calcoaceticus genes involved in biosynthesis of the coenzyme pyrrolo-quinoline-quinone: nucleotide sequence and expression in Escherichia coli K-12. J. Bacteriol. 1989;171:447-455
22.
Goosen N., Huinen R. G., van de Putte P. A 24-amino-acid polypeptide is essential for the biosynthesis of the coenzyme pyrrolo-quinoline-quinone. J. Bacteriol. 1992;174:1426-1427
23.
Hamagishi Y., Murata S., Kamei H., Oki T., Adachi O., Ameyama M. New biological properties of pyrroloquinoline quinone and its related compounds: inhibition of chemiluminescence, lipid peroxidation and rat paw edema. J. Pharmacol. Exp.Ther. 1990;255:980-985
24. Hevel J. M., Mills S. A., Klinman J. P. Mutation of a strictly conserved, active-site residue alters substrate specificity and cofactor biogenesis in a copper amine oxidase. Biochemistry 1999;38:3683-3693[Medline]
25. Hiraku Y., Kawanishi S. NADH-mediated DNA damage induced by a new coenzyme, pyrroloquinoline quinone, in the presence of copper(II) ion. FEBS Lett 1996;393:317-320[Medline]
26. Houck D. R., Hanners J. L., Unkefer C. J. Biosynthesis of Pyrroloquinoline Quinone. 1. Identification of biosynthetic precursors using 13C labeling and NMR spectroscopy. J. Am. Chem. Soc. 1988;110:6920-6921
27. Hultquist D. E., Xu F., Quandt K. S., Shlafer M., Mack C. P., Till G. O., Seekamp A., Betz A. L., Ennis S. R. Evidence that NADPH-dependent methemoglobin reductase and administered riboflavin protect tissues from oxidative injury. Am. J. Hematol. 1993;42:13-18[Medline]
28. Jensen R. G. eds. Handbook of Milk Composition 1995 Food Science and Technology International Series. Academic Press, Inc San Diego, CA.
29. Jensen F. E., Gardner G. J., Williams A. P., Gallop P. M., Aizenman E., Rosenberg P. A. The putative essential nutrient pyrroloquinoline quinone is neuroprotective in a rodent model of hypoxic/ischemic brain injury. Neurosci. Sep 1994;62(2):399-406
30. Kano K., Uno B., Kawasaki C., Horiki K., Kawai S. High performance liquid chromatographic determination of pyrroloquinoline quinone as acetone adduct. Analyt. Sci. 1991;7:737-739
31. Kenyon K., Modi W. S., Contente S., Friedman R. M. A novel human cDNA with a predicted protein similar to lysyl oxidase maps to chromosome-15q24-Q25. J. Biolog. Chem. 1993;268:18435-18437
32. Kumazawa T., Sato K., Seno H., Ishii A., Suzuki O. Levels of pyrroloquinoline quinone in various foods. Biochem. J. 1995;307:331-333
33. Kumazawa T., Seno H., Urakami T., Matsumoto T., Suzuki O. Trace levels of pyrroloquinoline quinone in human and rat samples detected by gas chromatography/mass spectrometry. Biochim. Biophys. Acta 1992;1156:62-66[Medline]
34.
Li W. D., Nellaiappan K., Strassmaier T., Graham L., Thomas K. M., Kagan H. M. Localization and activity of lysyl oxidase within nuclei of fibrogenic cells. Proc. Natl. Acad. Sci. USA. 1997;94:12817-12822
35.
Marini S., Giardina B., Fasciglione G. F., Finazzi-Agro A. Monoclonal antibody recognizes different quinone moieties in enzymes. J. Biol. Chem. 1993;268:13352-13355
36.
Matsushita K., Arents J. C., Bader R., Yamada M., Adachi O., Postma P. W. Escherichia coli is unable to produce pyrroloquinoline quinone (PQQ). Microbiology 1997;143:3149-3156
37. Matsuzaki R., Fukui T., Sato H., Ozaki Y., Tanizawa K. Generation of the topaquinone cofactor in bacterial monoamine oxidase by cupric ion-dependent autooxidation of a specific tyrosyl residue. FEBS Lett 1994;351:360-364[Medline]
38. McIntire W. S. Newly discovered redox cofactors: possible nutritional, medical and pharmacological relevance to higher animals. Ann. Rev. Nutr. 1998;18:145-177[Medline]
39. Meulenberg J. J., Sellink E., Riegman N. H., Postma P. W. Nucleotide sequence and structure of the Klebsiella pneumoniae pqq operon. Mol. Gen. Genet. 1992;232:284-294[Medline]
40. Mitchell A. E., Jones A. D., Mercer R. S., Rucker R. B. Characterization of pyrroloquinoline quinone amino acid derivatives by electrospray ionization mass spectrometry and detection in human milk. Analyt. Biochem. 1999;269:317-325
41.
Morris C. J., Biville F., Turlin E., Lee E., Ellermann K., Fan W. H., Ramamoorthi R., Springer A. L., Lidstrom M. E. Isolation, phenotypic characterization, and complementation analysis of mutants of Methylobacterium extorquens AM1 unable to synthesize pyrroloquinoline quinone and sequences of pqqD, pqqG and pqqC. J. Bacteriol. 1994;176:1746-1755
42.
Mu D., Medzihradszky K. F., Adams G. W., Mayer P., Hines W. M., Burlingame A. L., Smith A. J., Cai D., Klinman J. P. Primary structures for a mammalian cellular and serum copper amine oxidase. J. Biol. Chem. 1994;269:9926-9932
43. Murase K., Hattori A., Kohno M., Hayashi K. Stimulation of nerve growth factor synthesis/secretion in mouse astroglial cells by coenzymes. Biochem. Mol. Biol. Int. 1993;30:615-621[Medline]
44. Mure M., Tanizawa K. Chemical and biochemical characteristics of topa quinone. Biosci. Biotechnol. Biochem. 1997;61:410-417
45. Naito Y., Kumazawa T., Kino I., Suzuki O. Effects of pyrroloquinoline quinone (PQQ) and PQQ-oxazole on DNA synthesis of cultured human fibroblasts. Life Sci 1993;52:1909-1915[Medline]
46. Nakamura N., Matsuzaki R., Choi Y. H., Tanizawa K., Sanders-Loehr J. Biosynthesis of topa quinone cofactor in bacterial amine oxidases. Solvent origin of C-2 oxygen determined by Raman spectroscopy. J. Biolog. Chem. 1996;271:4718-4724
47. Nappi A. J., Vass E. The effects of glutathione and ascorbic acid on the oxidations of 6-hydroxydopa and 6-hydroxydopamine. Biochimica et Biophysica Acta 1994;1201:498-504[Medline]
48.
Narita H., Morishita E. Production and application of monoclonal antibodies specific to pyrroloquinoline quinone. J. Biochem. (Tokyo). 1995;117:830-835
49. Newcomer T. A., Rosenberg P. A., Aizenman E. TOPA quinone, a kainate-like agonist and excitotoxin is generated by a catecholaminergic cell line. J. Neurosci. 1995;15:3172-3177[Abstract]
50. Nishigori H., Ishida O., Ogihara-Umeda I. Preventive effect of pyrroloquinoline quinone (PQQ) on biliverdin accumulation of the liver of chick embryo after glucocorticoid administration. Life Sci 1993;52:305-312[Medline]
51. Nishigori H., Yasunaga M., Mizumura M., Lee J. W., Iwatsuru M. Preventive effects of pyrroloquinoline quinone on formation of cataract and decline of lenticular and hepatic glutathione of developing chick embryo after glucocorticoid treatment. Life Sci 1989;45:593-598[Medline]
52. Olsthoorn A. J., Duine J. A. Production, characterization, and reconstitution of recombinant quinoprotein glucose dehydrogenase (soluble type; EC 1.1.99.17) apoenzyme of Acinetobacter calcoaceticus. Arch. Biochem. Biophys. 1996;336:42-48[Medline]
53. Paz M. A., Martin P., Fluckiger R., Mah J., Gallop P. M. The catalysis of redox cycling by pyrroloquinoline quinone (PQQ), PQQ derivatives, and isomers and the specificity of inhibitors. Anal. Biochem. 1996;238:145-149[Medline]
54.
Pena M. M. O., Lee J., Thiele D. J. A delicate balance: Homeostatic control of copper uptake and distribution. J. Nutr. 1999;129:1251-1260
55.
Ren C., Yang G., Timme T. L., Wheeler T. M., Thompson T. C. Reduced lysyl oxidase messenger RNA levels in experimental and human prostate cancer. Cancer Res 1998;58:1285-1290
56. Rinaldi A. C., Porcu C. M., Oliva S., Curreli N., Rescigno A., Sollai F., Rinaldi A., Finazzi-Agro A., Sanjust E. Biosynthesis of the topaquinone cofactor in copper amine oxidases–evidence from model studies. Europ. J. Biochem. 1998;251:91-97[Medline]
57. Rinaldi A. C., Rescigno A., Rinaldi A., Sanjust E. Modeling novel quinocofactors: an overview. Bioorganic Chem 1999;27:253-288
58. Rucker R. B., Kosonen T., Clegg M. S., Mitchell A. E., Rucker B. R., Uriu-Hare J. Y., Keen C. L. Copper, lysyl oxidase, and extracellular matrix protein cross-linking. Am. J. Clin. Nutr. 1998;67(5 Suppl):996S-1002S[Abstract]
59. Rucker R. B., Rucker B. R., Mitchell A. E., Clegg M., Kosonen T., Uriu-Hare J., Tchaparian E. H., Keen C. L. Dietary copper: relationship to lysyl oxidase activity in chick tendon. J. Nutr. 1999;:in press
60. Ruggiero C. E., Dooley D. M. Stoichiometry of the topa quinone biogenesis reaction in copper amine oxidases. Biochemistry 1999;38:2892-2898[Medline]
61. Ruggiero C. E., Smith J. A., Tanizawa K., Dooley D. M. Mechanistic studies of topaquinone biogenesis in phenylethylamine oxidase. Biochemistry 1997;36:1953-1959[Medline]
62. Salisbury S. A., Forrest H. S., Cruse W. B., Kennard O. A novel coenzyme from bacterial primary alcohol dehydrogenases. Nature 1979;280:843-844[Medline]
63. Scanlon J. M., Aizenman E., Reynolds I. J. Effects of pyroloquinoline quinone on glutamate-induced production of reactive oxygen species in neurons. European J. Pharm. 1997;326:67-74
64. Schnider U., Keel C., Voisard C., Defago G., Haas D. Tn5-directed cloning of pqq genes from Pseudomonas fluorescens CHA0: mutational inactivation of the genes results in overproduction of the antibiotic pyoluteorin. Appl. Environ. Microbiol. 1995;61:3856-3864[Abstract]
65. Shah M. A., Bergethon P. R., Boak A. M., Gallop P. M., Kagan H. M. Oxidation of peptidyl lysine by copper complexes of pyrroloquinoline quinone and other quinones a model for oxidative pathochemistry. Biochimica et Biophysica Acta 1992;1159:311-318[Medline]
66. Shah M. A., Scaman C. H., Palcic M. M., Kagan H. M. Kinetics and stereospecificity of the lysyl oxidase reaction. J. Biolog. Chem. 1993;268:11573-11579
67. Smidt C. R., Bean-Knudsen D., Kirsch D. G., Rucker R. B. Does the intestinal microflora synthesize pyrroloquinoline quinone?. Biofactors 1991b;3:53-59[Medline]
68. Smidt C. R., Unkefer C. J., Houck D. R., Rucker R. B. Intestinal absorption and tissue distribution of [14C]pyrroloquinoline quinone in mice. Proc. Soc. Exp. Biol. Med. 1991a;197:27-31[Medline]
69. Steinberg F. M., Gershwin E., Rucker R. B. Dietary pyrroloquinoline quinone: growth and immune response in BALB/c mice. J. Nutr. 1994;124:744-753
70. Stites T. E., Mah J., Flueckiger R., Paz M., Gallop P., Rucker R. Dietary deficiency of pyrroloquinoline quinone (PQQ) alters mitochondrial function in young mice. FASEB J 1996;10:A800
71.
Tan R. S., Taniguchi T., Harada H. Identification of the lysyl oxidase gene as target of the antioncogenic transcription factor, IRF-1 and its possible role in tumor suppression. Cancer Res 1996;56:2417-2421
72.
Toyama H., Lidstrom M. E. pqqA is not required for biosynthesis of pyrroloquinoline quinone in Methylobacterium extorquens AM1. Microbiology 1998;144(Pt 1):183-191
73. Trackman P. C., Pratt A. M., Wolanski A., Tang S. S., Offner G. D., Troxler R. F., Kagan H. M. Cloning of rat aorta lysyl oxidase cDNA: complete codons and predicted amino acid sequence. Biochemistry 1990;29:4863-4870[Medline]
74. Trackman P. C., Pratt A. M., Wolanski A., Tang S. S., Offner G. D., Troxler R. F., Kagan H. M. Cloning of rat aorta lysyloxidase cDNA: complete codons and predicted amino acid sequence. Biochemistry 1991;30:8282[Medline]
75. Tsuchida T., Yasuyama T., Higuchi K., Watanabe A., Urakami T., Akaike T., Sato K., Maeda H. The protective effect of pyrroloquinoline quinone and its derivatives against carbon tetrachloride-induced liver injury of rats. J. Gastroenterol. Hepatol. 1993;8:342-347[Medline]
76. Urakami T., Yoshida C., Akaike T., Maeda H., Nishigori H., Niki E. Synthesis of monoesters of pyrroloquinoline quinone and imidazopyrroloquinoline, and radical scavenging activities using electron spin resonance in vitro and pharmacological activity in vivo. J. Nutr. Sci. Vitaminol. (Tokyo). 1997;43:19-33[Medline]
77. van der Meer R. A., Groen B. W., Van Kleef M. A. G., Frank J., Jongejan J. A., Duine J. A. Isolation, preparation and assay of pyrroloquinoline quinone. Meth. Enzymol. 1990;188:260-283[Medline]
78. Wang S. X., Nakamura N., Mure M., Klinman J. P., Sanders-Loehr J. Characterization of the native lysine tyrosylquinone cofactor in lysyl oxidase by Raman spectroscopy. J. Biolog. Chem. 1997;272:28841-28844
79. Watanabe A., Hobara N., Ohsawa T., Higashi T., Tsuji T. Nephrotoxicity of pyrroloquinoline quinone in rats. Hiroshima J. Med. Sci. 1989;38:49-51[Medline]
80. Xu F., Mack C. P., Quandt K. S., Shlafer M., Massey V., Hultquist D. E. Pyrroloquinoline quinone acts with flavin reductase to reduce ferryl myoglobin in vitro and protects isolated heart from re-oxygenation injury. Biochem. Biophys. Res. Commun. 1993;193:434-439[Medline]
81. Yamaguchi K., Sasano A., Urakami T., Tsuji T., Kondo K. Stimulation of nerve growth factor production by pyrroloquinoline quinone and its derivatives in vitro and in vivo. Biosci. Biotechnol. Biochem. 1993;57:1231-1233[Medline]
82. Zhang Z., Tillekeratne L. M., Kirchhoff J. R., Hudson R. A. High performance liquid chromatographic separation and pH-dependent electrochemical properties of pyrroloquinoline quinone and three closely related isomeric analogues. Biochem. Biophys. Res. Commun. 1995;212:41-47[Medline]
This article has been cited by other articles:
|
|
 |
|
  Y. B. Guo, J. Li, L. Li, F. Chen, W. Wu, J. Wang, and H. Wang Mutations That Disrupt Either the pqq or the gdh Gene of Rahnella aquatilis Abolish the Production of an Antibacterial Substance and Result in Reduced Biological Control of Grapevine Crown Gall Appl. Envir. Microbiol., November 1, 2009; 75(21): 6792 - 6803. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Choi, J. Kim, J.-G. Kim, Y. Jeong, J. S. Moon, C. S. Park, and I. Hwang Pyrroloquinoline Quinone Is a Plant Growth Promotion Factor Produced by Pseudomonas fluorescens B16 Plant Physiology, February 1, 2008; 146(2): 657 - 668. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Kaminaga, J. Schnepp, G. Peel, C. M. Kish, G. Ben-Nissan, D. Weiss, I. Orlova, O. Lavie, D. Rhodes, K. Wood, et al. Plant Phenylacetaldehyde Synthase Is a Bifunctional Homotetrameric Enzyme That Catalyzes Phenylalanine Decarboxylation and Oxidation J. Biol. Chem., August 18, 2006; 281(33): 23357 - 23366. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Stites, D. Storms, K. Bauerly, J. Mah, C. Harris, A. Fascetti, Q. Rogers, E. Tchaparian, M. Satre, and R. B. Rucker Pyrroloquinoline Quinone Modulates Mitochondrial Quantity and Function in Mice J. Nutr., February 1, 2006; 136(2): 390 - 396. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Traver, B. Salthun-Lassalle, M. Marien, E. C. Hirsch, F. Colpaert, and P. P. Michel The Neurotransmitter Noradrenaline Rescues Septal Cholinergic Neurons in Culture from Degeneration Caused by Low-Level Oxidative Stress Mol. Pharmacol., June 1, 2005; 67(6): 1882 - 1891. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Seshadri, G. S. A. Myers, H. Tettelin, J. A. Eisen, J. F. Heidelberg, R. J. Dodson, T. M. Davidsen, R. T. DeBoy, D. E. Fouts, D. H. Haft, et al. Comparison of the genome of the oral pathogen Treponema denticola with other spirochete genomes PNAS, April 13, 2004; 101(15): 5646 - 5651. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Steinberg, T. E. Stites, P. Anderson, D. Storms, I. Chan, S. Eghbali, and R. Rucker Pyrroloquinoline Quinone Improves Growth and Reproductive Performance in Mice Fed Chemically Defined Diets Experimental Biology and Medicine, February 1, 2003; 228(2): 160 - 166. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
