Pyrroloquinoline Quinone: A Novel Vitamin?

Lead Review Article October 1998: 287-293

Pyrroloquinoline Quinone: A Novel Vitamin? Amy Bishop, Ph.D., Paul M. Gallop, Ph.D., and Manli-ed L. Karnovsky, Ph.D.

Pyrroloquinoline quinone (PQQ), otherwise known as methoxatin, is a water-soluble, redox-cycling orthoquinone that was initially isolated from cultures of methylotropic bacteria. It has been found to be a cofactor of some bacterial alcohol dehydrogenases, and is present in many animal tissues. It may be a novel vitamin because it has been shown to be essential for normal growth and development. The redox-cycling ability of PQQ en- ables it to scavenge or generate superoxide. When fed to animals as a supplement, PQQ prevents oxidative changes that would ordinarily OCCUL It has been reported to inhibit glutamate decarboxylase activity and protect against N-methyl-D-aspartate (NMDA) receptor-mediated neurotoxicity in the brain. It appears that in the whole animal, however, PQQ does not cross the blood-brain barrier. Furthermore, it increases nerve growth factor (NGF) synthesis in mouse astroglial cells, but has to be bound to glycine to penetrate and exert this effect in whole brain. It may therefore be regarded as a Yanus faced molecule, with its potential for a therapeutic role in the brain still in question.

Discovery of PQQ

Pyrroloquinoline quinone (PQQ) was initially isolated fi-om cultures of methylotropic bacteria as a crystalline acetone adduct. It was found to be a cofactor of many bacterial primary alcohol dehydrogenases.' Its structure was de- duced from x-ray diffraction data and confirmed by organic synthesisZ (Figure 1). After the discovery of PQQ in bacteria, the search for PQQ in animal systems began.

Dr. Bishop is at the Department of Molecular and Cellular Toxicology, Harvard School of Public Health; Dr. Gallop (now deceased) was at the Laboratory of Human Biochemistry, Children's Hospital; and Dr. Karnovsky is at the Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 021 15, USA.

Presence of Native PQQ in Animal Systems and Cellular Extracts

In animal systems, PQQ was first thought to be a covalently bound cofactor of quinoprotein enzymes,= such as lysyl oxidase?JO Lysyl oxidase catalyzes covalent cross- linking in collagen and elastin by oxidatively deaminating peptidyl lysine to peptidyl a-aminoadipic aldehyde (allysine). The latter reacts across chains." In fact, many oxidases do not have PQQ itself as a cofactor but as a substance with a redox-cycling quinoid group that functions like PQQ.12J3 Although free PQQ in the presence of copper and oxygen can oxidize lysine residues in collagen to aldehydes, the reaction lacks the specificity of the en- zymatic process.1°

PQQ has bgen isolated from several mammalian biologic fluids such as plasma, synovial fluid, and bile at concentrations ranging from 50 to 500 pm~ledml. '" '~ It also is present at very high levels in milk and colostrum. Nursing rat dams supply their pups with high concentrations of PQQ, indicating that it has a role in neonatal de- ve10pment.l~ Chicken egg yolks and egg whites also contain high levels of PQQ consistent with the developing chick's need for PQQ.I5 Red cell hemolysates as well as neutrophils and monocytes contain dialyzable PQQ.16,18,19 The concentration of PQQ in the cytosol of neutrophils is 300 times that of the surrounding pla~rna. '~, '~ The native substance has been found in brain and cerebrospinal fluid

COOH

HOOC

0 PQQ

Figure 1. PQQ is a free, water-soluble, anionic compound. It is a redox-cycling planar orthoquinone.

Nutrition Reviews, Vol. 56, No. 10 287

Glycine (reduced) PQQ (reduced) Superoxide Formazan NH,-CH,-COOH-J [ QP(OH), I] [ 20; 1 [TH+H+

Glycine (oxidized) PQQ Oxygen Nitroblue Tetrazolium NH=CH-COOH QP(=O), 20, T+

Figure 2. The nitroblue tetrazolium assay (NBT) is the method of choice for detecting picomolar amounts of PQQ. The sample that contains PQQ is incubated with an excess of glycine, which reduces PQQ. The reduced PQQ goes on to reduce oxygen to superoxide, which reduces NBT to a formazan that is purple. The now oxidized PQQ is reduced by the excess glycine and can enter this cycle again. In this way, small amounts of PQQ can cycle and produce much forrnazan and, hence, be detected by colorimetric methods.

(CSF) of rats and humans.14 Of pathologic importance is the fact that patients with Parkinson’s disease have lower levels of PQQ in CSF and higher levels in blood serum than do healthy patients.I4J7 The CSF of aged rats has less PQQ than that of ordinary adult rats.l4

The aforementioned concentrations of PQQ were de- termined using a nitroblue tetrazolium (NBT) redox-cycling assay (Figure 2) as well as high-pressure liquid chromatography (HPLC).’”O It should be noted that the starting biologic sample was never lyophilized or stored for long periods of time, because native PQQ is sznsitive and easily lost. Kumazawa et a1.2’J2 demonstrated the presence of PQQ in various biologic tissues and foods with a different method. These researchers added phenyltrimethylammonium hydroxide (PTMA) to the tissue to derivatize native PQQ. The derivatized PQQ was then isolated from tissue lysates and analyzed by gas chromatography and mass spectrometry. This method allows for verification of the structure of the compound isolated, and it was indeed PQQ. This study conclusively and rig- orously demonstrated the presence of PQQ in animals.2’J2 The PQQ concentrations detected, however, were much lower than those found in the study using the redox-cycling assay.”I7 Perhaps the isolation procedures employed by Kumazawa et al. were destructive to PQQ or the derivatization was not complete.

Thus far, the PQQ present in animal systems has been proven to be a free, noncovalently linked cofactor of animal 0xidases.’”’~2~.~~ There is preliminary evidence that it is a dissociable cofactor of the reduced nicotinamide ad- enine dinucleotide OH)-ubiquinone reductase of complex 1 in mito~hondria.2~2~ Known mitochondrial poisons that inhibit the NADH-ubiquinone reductase of complex 1 in mitochondria (e.g., methylphenyl tetrahydropyridine W T P ] and rotenone) have been shown to bind PQQ in ~ i t r o . ~ ~ , * ~ Furthermore, aryl iodonium salts, such as diphenylene iodonium (DPI), that also have been shown to be strong complex 1 inhibitors, are specific inhibitors of PQQ redox c y ~ l i n g . 2 ~ ~ ~ These aryl iodonium compounds form adducts with PQQ that are stable and can be isolated and analy~ed.2~ A rigorous demonstration of the presence of PQQ in mitochondrial systems is still needed. Studies are required to isolate native PQQhnhibitor adducts from mitochondrial preparations and to verifi their structure

by mass spectroscopy and HPLC. There is some evidence for a role of PQQ in the flavin

reductase sytem, which is present in the heart and eryth- rocyte~?~ Preincubation of NADPH, PQQ, and flavin reductase in vitro resulted in a diminished formation of the damaging ferry1 myoglobin radical. In vitro, flavin reductase catalyzes the reduction of PQQ by NADPH. The reduced PQQ then goes on to reduce the ferrylmyoglobin radical to a functional ferrous myoglobin. Preincubation of hearts hung on a Langendorf apparatus with PQQ before the ischemicheperfusion insult lessened significantly the extent of injury.25 The protection that PQQ provides the heart fiom repefi ion injury suggests that native PQQ is the electron donor for this r edu~ tase .~~ Further studies are required to identifj a suitable antibody to PQQ for use in its detection in this and other reductases.

It has been discovered recently that PQQ is present in neutrophils and possibly involved in the “respiratory burstYylsJ9 of these cells when stimulated. In a stimulated neutrophil, superoxide anion is ~ecreted.2~2~ Agents that were shown to bind PQQ in vitro (4,5-dimethyl-lY2-phe- nylene diamine [DIMDA] and DPI) inhibited superoxide production by neutrophils and m o n o c y t e ~ . ~ ~ J ~ * ~ ~ , ~ ~ Ad- ducts of inhibitory agents and native PQQ were isolated from neutrophils and analyzed by HPLC.18J9 Peaks that had the same elution time and absorbance characteristics of a standard PQQ adduct were thought to be the native PQQ adduct. The inhibition of neutrophil superoxide production by DPI and DIMDA and subsequent isolation of a PQQ-DPI or PQQ-DIMDA adduct is a powerful method for establishing the role of PQQ in a cell. These findings, when considered with other in vitro studies by Xu et al.,25 which show that PQQ could take reducing equivalents fiom NADPH, suggest again that PQQ may be a dissociable cofactor of the neutrophil NADPH oxido-reductase system (Figure 3 9 At the very least, the data suggest that native PQQ is somehow involved in the neutrophil oxidative burst, but the mechanism is still not clear.

Absorption and Distribution of Exogenous PQQ in Mammalian Systems

The ability of mammals to absorb and distribute exogenous PQQ was examined to determine whether native

288 Nutrition Reviews, Vol. 56, No. 10

NADP+

0 NADPH

DPI DIMDA

0 2

k k

Flavoprotein

0;

DPI Figure 3. PQQ is a putative component of the phagocyte oxidative burst system. One place where PQQ perhaps exerts its effects is indicated. Reduced NADPH reduces PQQ(=O) to PQQ(2H). The PQQ(2H) then might reduce the flavoproteidcytochrome b complex, which can then reduce oxygen to superoxide. When the PQQ is sequestered by diphenylene iodonium . (DPI), this chain is blocked and no superoxide is produced. Dimethylphenylene diamine (DIMJlA) also sequesters PQQ, which blocks the chain, producing no superoxide.'* Inhibitors are italicized.

PQQ in animal tissues comes from dietary sources. PQQ was radiolabeled and given to mice orally.3O Most of it was absorbed by the gut. After 6 hours, much of the labeled PQQ was excreted in the urine, but a significant portion remained in the bloodstream, internalized by the red and white cells30 at concentrations suggesting that PQQ is brought into the cell via an active transport system rather than by passive diffu~ion. '~J~

Native PQQ as an Essential Nutrient in Animal Systems

A pivotal set of experiments performed by Smidt et al.31 and Killgore et al.32 demonstrated that PQQ is an essential nutrient in mammals and indicated that PQQ is at least partially obtained from dietary sources. Pregnant and nursing mice were made PQQ deficient. Antibiotics were added to the diet to kill intestinal flora, and the mice were reared in a sterile environment to eliminate the possibility of ob- taining PQQ from ba~ te r i a .~ ' .~~ The chow and water were assayed for PQQ to make sure the diet was completely PQQ free.3'~~~ The PQQ-deficient female mice, when mated, were found to be sterile or, when successfully impreg- nated, to have litters that were cannibalized at birth.32 Clearly, the health of the adult animal is impacted nega- tively by PQQ deficiency. Eight of the 40 deprived offspring died of aortic aneurysms or abdominal hemorrhages after 8 weeks of PQQ deprivati~n.~~ Surviving offspring of PQQ-deficient dams exhibited fiiable skin, alopecia, and a hunched p o ~ t u r e . ~ ' , ~ ~ When PQQ-deprived pregnant mice were given supplementary PQQ (800 nglg diet), their offspring were normal in ap~earance.~'J~

The results of these studies support the importance of PQQ in normal neonatal development. In the offspring, PQQ deprivation resulted in decreased cross-linking of collagen and ela~tin.~'J* The deprived mice had only 10% to 30% the level of lysyl oxidase of normal mice.32 The data, when considered with the study of Shah et al.,'O further implicate PQQ as a free cofactor of lysyl oxidase. These physiologic effects of PQQ deficiency are reminis-

cent of osteolathyrism, a condition brought about by a diet high in the chickling pea (Lathyrus odoratus) in which the toxic agent is P-amin~propionitrile.~~ Interestingly, aminonitriles, such as P-aminopropionitrile, are antago- nists of PQQ in the NBT-formazan system.I6

Studies also have demonstrated decreased immunity in PQQ-deficient mice.30 Splenocytes from 20-week-old mice were cultured in the presence of the T-cell mitogen, concanavalin A, and the B-cell mitogen, lipopolysaccha- ride. The degree of cellular mitosis stimulated by the mito- gens was assayed by incorporation of [3H] thymidine into the cellular DNA. Mice that received < 200 ng PQQ/g diet had splenocytes with depressed mitotic ability. This de- pression was not reversible upon administration of PQQ to the PQQ-deprived mice.3O The data, when considered with the aforementioned neutrophil data, imply that PQQ is important for immunity.

The splenocyte study is particularly revealing when coupled with results of Naito et al.," who added PQQ to human fibroblasts and scored mitogenicity by rate of [3H] thymidine incorporation. As little as 3 nM PQQ increased fibroblast transcription, but the oxazole of PQQ (glycine- PQQ adduct) had no effect on mitosis." (The oxazole form of PQQ results when free PQQ undergoes a condensation reaction with an a-amino acid.) This form of PQQ has a blocked redox site, suggesting that the latter is the active locus for mitogenicity of PQQ. This evidence indicates that dietary PQQ is involved in collagen cross-linking, skin integrity, and normal immune fimction. The deficiency experiments indicate that PQQ might be a novel vitamin or an essential nutrient. A study by Kosano et al?5 found that PQQ also can block transcription; 3 nM PQQ inhibited the induction of tyrosinase transcription by melanocyte-stimulating hormone (MSH), thus inhibiting melano- genesis.

PQQ as a Generator of Superoxide

PQQ can generate superoxide when given a source of elec- trons, such as NADPH, glycine, other amines, thiol com-


pounds, or a ~ c o r b a t e . ~ ~ . ~ ~ Under alkaline conditions, the PQQ as a Scavenger of Superoxide orthoquinone form of PQQ oxidizes glycine, thus converting PQQ to its semiquinone and hydroquinone forms. The semiquinone and hydroquinone forms of PQQ then reduce oxygen to superoxide. This property of PQQ is the basis for the NBT-formazan assay for PQQ (Figure 2),36,37 as discussed above.

Exogenous PQQ Protects Against Oxidative Damage in Animals

In several mammalian systems in vivo, exogenous PQQ at high concentrations functions as an antioxidant. An intraperitoneal injection of PQQ protected rats from liver damage caused by various hepatotoxic substances, including carbon tetrachloride, D-galactosamine, thioacetamide, and ally1 f ~ r m a t e . ~ ~ After the degree of liver damage was measured, the increase in serum levels of bilirubin and glutamic- pyruvic transaminase was measured, as was the increase in liver triglycerides and lipid peroxidation. PQQ (1 1.5 mg/ kg) given within 6 hours after the administration of the toxic substance had a significant protective effect? PQQ also protected cultured hepatocyes from damage from carbon tetra~hloride.~~ (This level of PQQ is high compared with physiologic levels.)

Rats injected intraperitoneally with PQQ also were protected against liver damage caused by ethanol loading.40 Metabolism of ethanol yields the damaging intermediate acetaldehyde. Animals given ethanol without PQQ pretreatment had higher acetaldehyde levels in their blood and liver compared with PQQ-treated animals. The rate of ethanol oxidation to acetaldehyde, however, was about the same in treated and untreated animals. PQQ decreased levels of acetaldehyde by increasing the rate at which it is oxidized to acetate rather than by decreasing the rate of acetaldehyde production.'"'

PQQ also functions as an anti-inflammatory agent in rats.41 When rats received an injection of carrageenan into one of their paws, an increase in local edema and tempera- ture-indicative of an inflammatory response-resulted. When they also received PQQ (3 1.5 pg/mL) intravenously before treatment with carrageenan, the inflammatory reaction was decreased:'

The study by Nishigori et al." supports the hypo- thesis that PQQ protects against oxidative stress without depleting the cell's reducing equivalents. When chicks received injections of hydrocortisone, severe cataracts formed and reduced glutathione (GSH) levels were decreased in both the lens and the liver. Chicks that received PQQ before hydrocortisone treatment exhibited much less cataract formation and had stable GSH levels in the liver and the lens. Of note is that when the chicks received PQQ alone, the amount of GSH increased in both the liver and the Supplementation with high amounts of PQQ protects animals from oxidative stress-induced damage.

In the aforementioned animal systems, PQQ has been shown to exert its protective effect by conserving reducing equivalents such as GSH.42 It is classically thought that a cell uses superoxide dismutase (SOD) to remove potentially damaging superoxide by converting superoxide to hydrogen peroxide via a dismutase reaction." How- ever, hydrogen peroxide is damaging and is removed by two reactions. It can be broken down to water and oxygen by catalase,- and it also can be scavenged by the oxidation of GSH to oxidized glutathione (GSSG).45 Scavenging of peroxide by the glutathione pathway depletes the cell's available reducing equivalents."

PQQ theoretically can scavenge superoxide and peroxide without depletion of the cell's reducing equiva- l e n t ~ . ' ~ ' ~ , ~ ~ If there is excess superoxide and peroxide in the system, PQQ scavenges them by oxidizing the superoxide anion to oxygen.lSl7 This reduced PQQ can donate its reducing equivalents to NADP' and convert it to NADPH. The NADPH can then be used to reduce GSSG to GSH. Instead of taking reducing equivalents from NADPH, as PQQ does when it generates su~e rox ide ,~~ PQQ donates reducing equivalents. The reactions occur according to the following two equations:

(1)

Thus, scavenging of superoxide with PQQ is less expen- sive to the reducing economy of the cell than the classic scavenging system. 15-17

PQQ(2H) + NADP + NADPH +H+ + PQQ, NADPHTH++ GSSG+2GSH+NADI?. (2)

PQQ in the Brain

PQQ is of particular importance in the brain. In vitro experiments demonstrated its ability to inhibit the action of porcine brain 4-aminobutyrate aminotransferase by oxidizing its dithiol gr0up.4~PQQ also has been shown to inhibit glutamate decarboxylase in the porcine It has been proposed that native PQQ in the brain would inhibit these enzymes in viv0.4~3~~ Because glutamate decarboxylase removes the carboxyl group from glutamate and yields y-aminobutyric acid (GABA), one might imag- ine that its inhibition by high levels of PQQ in the brain might result in increased glutamate levels. The increased glutamate levels would overstimulate NMDA receptors, causing production of the free radicals nitric oxide and superoxide, which then, by themselves or as a peroxynitrite anion, cause oxidative damage that leads to cell

Paradoxically, PQQ seems to protect astrocyte-rich cortical neuron cultures against NMDA receptor-mediated glutamate ex~ i to tox ic i ty .~~~~~ Glutamate toxicity was significantly diminished when neurons were pretreated with PQQ (1 6.5 pg/mL).48*49 The ability of PQQ to protect against excitotoxicity was inhibited by an agent that alky- lates thiol groups (N-ethyl maleimide). It was inferred from

290 Nutrition Reviews, Vol. 56, No. 10

this that PQQ exerted its effects on the dithiol redox modulatory group on the NMDA re~eptor .4~*~~ In fact, PQQ in vitro has been shown to oxidize thiol groups (see ab0ve).4~A~ The alkylating agent may block other sites of action for PQQ or it may interact with PQQ itself and in this way inhibit its action. However, in light of the fact that PQQ increases glutamate levels, it is puzzling that PQQ would protect against rather than exacerbate glutamate toxicity.

Intraperitoneal injection of an extremely high dose of PQQ (1 0 mg/kg) also appears to protect against hypoxic/ ischemic injury and seizure activity in the neonatal rat stroke model. The damage from stroke may be caused by NMDA receptor-mediated excitotoxicity.sO In the whole animal, the protective effect exerted by PQQ may be through its ability to scavenge the free radicals produced by NMDA receptor-mediated excitotoxicity rather than by its ability to oxidize the redox modulatory region on the NMDA receptor itself.

Because PQQ scavenges superoxide in high-superoxide conditions and generates superoxide in low-saper- oxide conditions, there is a question of the appropriate redox form of PQQ entering a stroked brain and specifi- cally affecting the infarcted area.1sJ8J9,37 Perhaps the PQQ- mediated diminution of the infarcted area in stroke brains is due to PQQ decreasing the damage to the infarcted tissue while causing damage to the surrounding nonin- farcted tissues, thus smearing the border between the in- farction and healthy tissue and giving the false appear- ance of amelioration.

PQQ has been shown to stimulate the synthesis of nerve growth factor (NGF) in mouse astroglial cell^.^' Free PQQ increased the production of NGF in vitro but not in vivo. The oxazole of PQQ increased the total brain con- tent ofNGF in rats, whereas fiee PQQ did not.5' The oxazole derivatization allowed PQQ to cross the blood-brain barrier to exert its effects on NGF synthesis. PQQ in its free form cannot cross the blood-brain barrier and has no effect, perhaps for that reas~n.~ '*~*

The observation that free PQQ cannot cross the blood-brain barrier puts the animal stroke model into question. One might wonder how PQQ can exert its protective effects in the stroke model when it cannot reach the brain. The rat pups used for the stroke model may have been young enough to have an incomplete blood-brain barrier.

Implications

In summary, PQQ is a dietary component that is absorbed by animals. This component is normally excreted in high concentrations in colostrum and milk, which might indicate that it is needed by the neonate. When animals are deprived of PQQ, there is reduced health and reproduc- tive ability in adults and loss of viability in neonates. When PQQ is administered in large amounts, it provides signifi-

cant protection against oxidative stress. Current research provides strong evidence that PQQ may be considered a novel vitamin required by adult animals for health and by neonates for survival.

Acknowledgment. This work was supported by grants from the National Institutes of Health and was partially funded by the National Dairy Promotion and Research Board and administered in cooperation with the National Dairy Council.

Dedication. This review is dedicated to the memory of Dr. Paul M. Gallop, who saw earlier versions of this paper and was the first to discover PQQ in animal systems. He was a careful yet bold scientist who will be re- membered as one of the great pioneers. Paul pursued knowledge for its own sake and collaborated to advance answers to a question rather than to advance himself. He was generous with his time and ideas and he was a great mentor and friend.

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Pyrroloquinoline Quinone: A Novel Vitamin?

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