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PubMed1989

Reaction of pyridoxamine-5-P with pyrroloquinoline quinone (coenzyme PQQ).

PQQ catalyzes the oxidation of pyridoxamine (PM) and pyridoxamine-5-P (PMP) to pyridoxal and pyridoxal-5-P (PLP) at 37 degrees C in the absence of micelles and proteins. The time course of conversion of PMP into PLP was monitored by absorption spectroscopy; a rate of 10 nmol PLP/min was determined. The product of the reaction was identified by TLC, HPLC and its ability to restore the catalytic activity of apoaspartate aminotransferase. The conversion of PMP into PLP by free PQQ is more efficient than reactions catalyzed by the enzymes plasma amine oxidase and pyridoxamine-5-P oxidase at optimal pH values.

Animals↗
PubMed1988

Pyrroloquinoline quinone: excretion by methylotrophs and growth stimulation for microorganisms.

A marked excretion of pyrroloquinoline quinone (PQQ) by methylotrophs into the culture medium was observed when incubation was prolonged to the late stationary phase. When the organisms were growing vigorously in the early exponential phase, accumulation of PQQ was repressed at a low level. Some evidence was obtained that the excretion of PQQ is related to turnover of quinoproteins of the organisms. The growth stimulation of microorganisms by PQQ was demonstrated using Acetobacter aceti. The presence of PQQ even at the pg/ml level in the culture medium stimulated the bacterial growth by reducing the lag time. The growth stimulating effect of PQQ was observed only by the reduction of the lag time but not by increase in either the subsequent growth rate or the total cell yield. The results indicated that PQQ must have an important role in the initiation of cell reproduction.

Acetobacter↗
PubMed1988

Adduct formation of pyrroloquinoline quinone and amino acid.

When pyrroloquinoline quinone (PQQ) is mixed with an amino acid, a corresponding Schiff base PQQ adduct is readily formed between carbonyl groups of PQQ and the primary amino group. A potent growth stimulating effect for microorganisms was observed with the PQQ adduct when it was administered in a culture medium. Although PQQ itself shows a marked growth stimulating effect, PQQ adducts appeared to be more active than authentic PQQ when compared on a molar basis. Conversely, unlike authentic PQQ, PQQ adducts were shown to be less active (greater than or equal to 100-fold) as the prosthetic group for a quinoprotein apo-glucose dehydrogenase when examined by holoenzyme formation by exogenous addition of PQQ or PQQ adducts. These observations suggested that PQQ adduct formation readily occurs during isolation procedures for PQQ from biological materials or PQQ - chromophore from quinoproteins. Therefore, the presence of such adducts gives a PQQ estimation much lower than theoretically expected. As an example, formation, isolation and characterization of PQQ - serine are described.

Amino Acids↗
PubMed1987

PQQ-linked enzymes in enteric bacteria.

Klebsiella aerogenes possesses a PQQ-linked glucose dehydrogenase. Other members of the Enterobacteriaceae, such as Escherichia coli, Salmonella typhimurium or Serratia marcescens are seemingly unable to synthesize PQQ, but are able to synthesize the glucose dehydrogenase apoenzyme. The physiological significance of this enzyme is discussed.

Coenzymes↗
PubMed1993

Monoclonal antibody recognizes different quinone moieties in enzymes.

We produced monoclonal antibodies against the coenzyme pyrrolequinoline quinone (PQQ). These antibodies were obtained by immunizing mice with PQQ conjugated to a chemically modified polypeptide in order to induce a strong immune response. Among the various antibodies obtained, one was found to bind (besides PQQ and 6-hydroxydopamine conjugated to carrier proteins) several different quinoenzymes, namely lentil seedling and bovine serum diamine oxidases and methylamine dehydrogenase. This antibody was able to inhibit the catalytic activity of these enzymes. Moreover, the monoclonal antibody recognized different proteins of lentil seeds on Western blots. Even the variable fragment of immunoglobulin heavy chains of this monoclonal antibody expressed in Escherichia coli is able to recognize the active site of different quinoenzymes.

Amine Oxidase (Copper-Containing)↗
PubMed1993

Stimulation of nerve growth factor synthesis/secretion in mouse astroglial cells by coenzymes.

We examined the effect of coenzymes such as PQQ, pyrroloquinoline quinone; TOPA, 3-(2,4,5-trihydroxyphenyl)-DL-alanine, and lipoic acid on nerve growth factor (NGF) synthesis in mouse astroglial cells, BALB c/3T3 cells, and WS-1 cells in culture. These coenzymes had a stimulating effect on NGF synthesis without causing cytotoxicity. Especially PQQ showed the strongest activity of promoting NGF synthesis in astroglial cells, whereas lipoic acid had the strongest effect on BALB c/3T3 cells. The activity may not due to the catechol ring or 1,4-benzoquinone ring, but due to the oxidative or reductive activity. These results suggest that these coenzymes may play a role in NGF synthesis and neuronal survival through the stimulating effect of the NGF synthesis in brain and such compounds are good candidates as NGF inducers.

3T3 Cells↗
PubMedDate not supplied

PQQ as redox shuttle for quinoprotein glucose dehydrogenase.

The role of pyrroloquinoline quinone (PQQ) as a redox shuttle between an electrode and the active site of soluble quinoprotein glucose dehydrogenase (sGDH) from Acinetobacter calcoaceticus has been investigated using both electrochemical and spectrophotometric methods. Reversible redox behavior of PQQ was observed at cystamine-modified gold electrodes. sGDH is able to reduce free PQQ, i.e. PQQ that is not bound to the enzyme and therefore could act as a mediator between the enzyme and the cystamine-modified electrode. The second order rate constants for the reduction of PQQ by sGDH are 6 x 10(3) M(-1) S(-1) and 64 M(-1) S(-1) in the absence and in the presence of calcium ions, respectively. Similarly, the interaction with a second redox protein is realized via the PQQ shuttle. Using DC voltammetry, the reduction rate of cytochrome c (cyt c) by PQQH2 was determined to be on the order of 10(4) M(-1) S(-1)

Acinetobacter↗
PubMed1989

Factors relevant in bacterial pyrroloquinoline quinone production.

Quinoprotein content and levels of external pyrroloquinoline quinone (PQQ) were determined for several bacteria under a variety of growth conditions. From these data and those from the literature, a number of factors can be indicated which are relevant for PQQ production. Synthesis of PQQ is only started if synthesis of a quinoprotein occurs, but quinoprotein synthesis does not depend on PQQ synthesis. The presence of quinoprotein substrates is not necessary for quinoprotein and PQQ syntheses. Although the extent of PQQ production was determined by the type of organism and quinoprotein produced, coordination between quinoprotein and PQQ syntheses is loose, since underproduction and overproduction of PQQ with respect to quinoprotein were observed. The results can be interpreted to indicate that quinoprotein synthesis depends on the growth rate whereas PQQ synthesis does not. In that view, the highest PQQ production can be achieved under limiting growth conditions, as was shown indeed by the much higher levels of PQQ produced in fed-batch cultures compared with those produced in batch experiments. The presence of nucleophiles, especially amino acids, in culture media may cause losses of PQQ due to transformation into biologically inactive compounds. Some organisms continued to synthesize PQQ de novo when this cofactor was administered exogenously. Most probably PQQ cannot be taken up by either passive diffusion or active transport mechanisms and is therefore not able to exert feedback regulation on its biosynthesis in these organisms.

Alcohol Oxidoreductases↗
PubMed1988

Bacterial NAD(P)-independent quinate dehydrogenase is a quinoprotein.

Acinetobacter calcoaceticus LMD 79.41 produced significant amounts of pyrrolo-quinoline quinone (PQQ) in its culture medium when grown on quinic acid or shikimic acid. Studies with LMD 79.41 and PQQ- -mutants of this strain demonstrated that this organism contains an NAD(P)-independent quinate dehydrogenase (QDH) (EC 1.1.99.-), catalyzing the first degradation step of these compounds, and that the enzyme contains PQQ as a cofactor, i.e. is a quinoprotein. Synthesis of QDH was induced by protocatechuate and the enzyme appeared to be particle-bound. Acinetobacter Iwoffi RAG-1 produced a quinoprotein QDH apoenzyme since growth on quinic acid only occurred in the presence of PQQ. The results obtained with the PQQ- -mutants of strain LMD 79.41 also provided some insight into the regulation of PQQ biosynthesis and assemblage of quinoprotein enzymes in the periplasmic space. Since two species of Pseudomonas also contained a quinoprotein QDH, it is assumed that bacterial NAD(P)-independent quinate dehydrogenase is a quinoprotein.

Acinetobacter↗
PubMed1989

Studies on the active site of pig plasma amine oxidase.

Amine oxidase from pig plasma (PPAO) has two bound Cu2+ ions and at least one pyrroloquinoline quinone (PQQ) moiety as cofactors. It is shown that recovery of activity by copper-depleted PPAO is linear with respect to added Cu2+ ions. Recovery of e.s.r. and optical spectral characteristics of active-site copper parallel the recovery of catalytic activity. These results are consistent with both Cu2+ ions contributing to catalysis. Further e.s.r. studies indicate that the two copper sites in PPAO, unlike those in amine oxidases from other sources, are chemically distinct. These comparative studies establish that non-identity of the Cu2+ ions in PPAO is not a requirement for amine oxidase activity. It is shown through the use of a new assay procedure that there are two molecules of PQQ bound per molecule of protein in PPAO; only the more reactive of these PQQ moieties is required for activity.

Amine Oxidase (Copper-Containing)↗
PubMed2006

Pyrroloquinoline quinone (PQQ) prevents fibril formation of alpha-synuclein.

Pyrroloquinoline quinone (PQQ) is a noncovalently bound cofactor in the bacterial oxidative metabolism of alcohols. PQQ also exists in plants and animals. Due to its inherent chemical feature, namely its free-radical scavenging properties, PQQ has been drawing attention from both the nutritional and the pharmacological viewpoint. alpha-Synuclein, a causative factor of Parkinson's disease (PD), has the propensity to oligomerize and form fibrils, and this tendency may play a crucial role in its toxicity. We show that PQQ prevents the amyloid fibril formation and aggregation of alpha-synuclein in vitro in a PQQ-concentration-dependent manner. Moreover, PQQ forms a conjugate with alpha-synuclein, and this PQQ-conjugated alpha-synuclein is also able to prevent alpha-synuclein amyloid fibril formation. This is the first study to demonstrate the characteristics of PQQ as an anti-amyloid fibril-forming reagent. Agents that prevent the formation of amyloid fibrils might allow a novel therapeutic approach to PD. Therefore, together with further pharmacological approaches, PQQ is a candidate for future anti-PD reagent compounds.

Amyloid↗
PubMed1998

Reconstitution of membrane-integrated quinoprotein glucose dehydrogenase apoenzyme with PQQ and the holoenzyme's mechanism of action.

Membrane-integrated quinoprotein glucose dehydrogenase from Acinetobacter calcoaceticus was produced by heterologous expression of the gene for it in an Escherichia coli recombinant strain. The apoenzyme (lacking the cofactor pyrroloquinoline quinone, PQQ) was solubilized with Triton X-100 and purified to homogeneity. Reconstitution of the apoenzyme to full activity in the assay was achieved with a stoichiometric amount of PQQ in the presence of Mg2+. Just as for other PQQ-containing dehydrogenases where Ca2+ fulfills this role, Mg2+ anchors PQQ to the mGDH protein and activates the bound cofactor. This occurs in a precise way since high anomer specificity was found for the enzyme toward the sugars tested. Although the steady-state-type kinetics were as expected for a dye-linked dehydrogenase (ping-pong) and the PQQ in it was present in oxidized form, addition of glucose to the holoenzyme resulted in a very slow but continuous production of gluconolactone; i.e., the reaction did not stop after one turnover, with O2 apparently acting as an (albeit poor) electron acceptor by reoxidizing PQQH2 in the enzyme. The surprisingly low reactivity with glucose, in the absence of dye, as compared to the activity observed in the steady-state assay appeared to be due to formation of an anomalous enzyme form, mGDH. Formation of normal holoenzyme, mGDH, reducing added glucose immediately to gluconolactone (in one turnover), was achieved by treating mGDH with sulfite, by reconstituting apoenzyme with PQQ in the presence of sulfite, or by applying assay conditions to mGDH (addition of PMS/DCPIP). As compared to other quinoprotein dehydrogenases, mGDH appears to be unique with respect to the mode of PQQ-binding, as expressed by the special conditions for reconstitution and the absorption spectra of the bound cofactor, and the reactivity of the reduced enzyme toward O2. The primary cause for this seems not to be related to a different preference for the activating bivalent metal ion but to the special way of binding of PQQ to mGDH.

Animals↗
PubMed1991

Does the intestinal microflora synthesize pyrroloquinoline quinone?

Pyrroloquinoline quinone (PQQ) functions as a cofactor for prokaryotic oxidoreductases, such as methanol dehydrogenase and glucose dehydrogenase. When chemically-defined diets without PQQ are fed to animals, lathyritic changes are observed. In previous studies, it was assumed that PQQ was produced by the intestinal microflora; consequently, antibiotics were routinely added to diets. In the present study this assumption is tested further in mice by: (i) examining the effects of dietary antibiotics on fecal PQQ excretion, (ii) isolating the intestinal flora to identify bacteria known to synthesize PQQ and (iii) determining in vitro if the intestinal microflora synthesizes PQQ from radio-chemically labeled precursors. The results of these experiments indicate that little if any PQQ is synthesized by the intestinal microflora. Rather, when PQQ is present in the intestine, the diet is a more obvious source.

Animals↗
PubMed1999

Structure and mechanism of soluble quinoprotein glucose dehydrogenase.

Soluble glucose dehydrogenase (s-GDH; EC 1.1.99.17) is a classical quinoprotein which requires the cofactor pyrroloquinoline quinone (PQQ) to oxidize glucose to gluconolactone. The reaction mechanism of PQQ-dependent enzymes has remained controversial due to the absence of comprehensive structural data. We have determined the X-ray structure of s-GDH with the cofactor at 2.2 A resolution, and of a complex with reduced PQQ and glucose at 1.9 A resolution. These structures reveal the active site of s-GDH, and show for the first time how a functionally bound substrate interacts with the cofactor in a PQQ-dependent enzyme. Twenty years after the discovery of PQQ, our results finally provide conclusive evidence for a reaction mechanism comprising general base-catalyzed hydride transfer, rather than the generally accepted covalent addition-elimination mechanism. Thus, PQQ-dependent enzymes use a mechanism similar to that of nicotinamide- and flavin-dependent oxidoreductases.

Binding Sites↗
PubMed1994

Conversion of acetyl-coenzyme A into 3-hydroxy-3-methylglutaryl-coenzyme A in radish seedlings. Evidence of a single monomeric protein catalyzing a FeII/quinone-stimulated double condensation reaction.

We solubilized from radish membranes and purified to apparent homogeneity a monomeric protein (55.5 kDa) capable of catalyzing the two-step conversion of acetyl-CoA into 3-hydroxy-3-methylglutaryl(HMG)-CoA. Unlike the situation described for other eukaryotes (yeast, animals), both enzyme activities needed for HMG-CoA synthesis (acetoacetyl-CoA thiolase, AACT and HMG-CoA synthase, HMGS) appear to be localized on a single polypeptide. Thus, the enzyme system is further referred to as AACT/HMGS. The reaction as catalyzed by purified AACT/HMGS is strongly stimulated in vitro in presence of FeII-chelates (namely EDTA) and of quinone cofactors with pyrroloquinoline quinone (PQQ) being by far the most effective one studied so far. Whereas the FeII stimulation is apparently due to a Vmax effect, PQQ increases the affinity of the enzyme system towards acetyl-CoA (1.9 microM vs. 5.9 microM, at 50 microM FeII, 100 microM EDTA, 20 microM PQQ). Stimulation by naphthoquinone (NQ) can be overcome in the presence of halogenated NQ-derivatives, while activation by PQQ remains unaffected, possibly indicating a much more specific-binding of the latter cofactor. Gel filtration experiments of enzyme after preincubation in presence of PQQ indicate that there is no covalent-binding of the quinone cofactor to the enzyme. As is also shown with partially purified enzyme from maize membranes, phenylhydrazine, known to react with PQQ as the prosthetic group of quinoproteins (see van der Meer et al. (1987) FEBS Lett. 221, 299-304), efficiently inhibits the reaction. The data lead us to suggest a reaction mechanism that involves radical formation by the redox couple FeII/PQQ, thereby possibly facilitating the energetically unfavorable Claisen condensation as catalyzed during the first partial (AACT) reaction.

Acetyl Coenzyme A↗
PubMed2006

Knockout and overexpression of pyrroloquinoline quinone biosynthetic genes in Gluconobacter oxydans 621H.

In Gluconobacter oxydans, pyrroloquinoline quinone (PQQ) serves as the cofactor for various membrane-bound dehydrogenases that oxidize sugars and alcohols in the periplasm. Proteins for the biosynthesis of PQQ are encoded by the pqqABCDE gene cluster. Our reverse transcription-PCR and promoter analysis data indicated that the pqqA promoter represents the only promoter within the pqqABCDE cluster of G. oxydans 621H. PQQ overproduction in G. oxydans was achieved by transformation with the plasmid-carried pqqA gene or the complete pqqABCDE cluster. A G. oxydans mutant unable to produce PQQ was obtained by site-directed disruption of the pqqA gene. In contrast to the wild-type strain, the pqqA mutant did not grow with d-mannitol, d-glucose, or glycerol as the sole energy source, showing that in G. oxydans 621H, PQQ is essential for growth with these substrates. Growth of the pqqA mutant, however, was found with d-gluconate as the energy source. The growth behavior of the pqqA mutant correlated with the presence or absence of the respective PQQ-dependent membrane-bound dehydrogenase activities, demonstrating the vital role of these enzymes in G. oxydans metabolism. A different PQQ-deficient mutant was generated by Tn5 transposon mutagenesis. This mutant showed a defect in a gene with high homology to the Escherichia coli tldD gene, which encodes a peptidase. Our results indicate that the tldD gene in G. oxydans 621H is involved in PQQ biosynthesis, possibly with a similar function to that of the pqqF genes found in other PQQ-synthesizing bacteria.

Bacterial Proteins↗