Pyrroloquinoline-Quinone Is More Than an Antioxidant: A Vitamin-like Accessory Factor Important in Health and Disease Prevention

Abstract

Pyrroloquinoline quinone (PQQ) is associated with biological processes such as mitochondriogenesis, reproduction, growth, and aging. In addition, PQQ attenuates clinically relevant dysfunctions (e.g., those associated with ischemia, inflammation and lipotoxicity). PQQ is novel among biofactors that are not currently accepted as vitamins or conditional vitamins. For example, the absence of PQQ in diets produces a response like a vitamin-related deficiency with recovery upon PQQ repletion in a dose-dependent manner. Moreover, potential health benefits, such as improved metabolic flexibility and immuno-and neuroprotection, are associated with PQQ supplementation. Here, we address PQQ's role as an enzymatic cofactor or accessory factor and highlight mechanisms underlying PQQ's actions. We review both large scale and targeted datasets demonstrating that a neonatal or perinatal PQQ deficiency reduces mitochondria content and mitochondrial-related gene expression. Data are reviewed that suggest PQQ's modulation of lactate acid and perhaps other dehydrogenases enhance NAD+-dependent sirtuin activity, along with the sirtuin targets, such as PGC-1α, NRF-1, NRF-2 and TFAM; thus, mediating mitochondrial functions. Taken together, current observations suggest vitamin-like PQQ has strong potential as a potent therapeutic nutraceutical.

Keywords: PQQ; antioxidant; cell signaling; inflammation; nutrition; pyrroloquinoline quinone; vitamins.

Figure 1

PQQ and electron transfer reactions. PQQ, in its reduced state, efficiently catalyzes electron transfer reactions. Potential substrates range from organic radicals to radical forms of oxygen. For many of the PQQ—dependent dehydrogenase systems, electron transfer may involve a heme-associated component. PQQ is reduced in reactions, utilizing either NAD[P]H, thiols such as cysteine and glutathione, enediols such as ascorbic acid, or aroxyl radical reductants such as the tocopherols.

Figure 2

PQQ and cellular NAD⁺. Events elicited by PQQ and NAD+ are highlighted. At the top of the figure, A, niacin-related serum components are depicted that are important in the production of NAD+. Each interacts to generate NAD+ as indicated in the section encircled as B. PQQ plays a role in the process by enhancing the expression of nicotinamide phosphoribosyltransferase (designated as Nampt}. Increasing Nampt activity increases NAD+ cellular levels. NAD+ performs two principal functions; first, as a cofactor for dehydrogenases and reductases, such as lactic acid dehydrogenase (LDH), C, and second, as a co-substrate for sirtuin-catalyzed protein deacetylations as noted in D. Likewise, PQQ is a catalytic cofactor for LDH, C. PQQ facilitates the conversion of lactate to pyruvate. In the nucleus, E, NAD+, as a co-substrate for sirtuins, promotes targeted acetylation or deacetylation of proteins involved in cell signaling. Six examples are enumerated: (1) the LKBl/AMP-Kinase-pathway, important in the regulation of rnitochondriogenesis and rates of P-oxidation, (2) Forkhead box 0 transcription factors (FoxO) important to cellular proliferation and survival, (3) transcription factors involving NF-KB and P53 proteins, which regulate multiple aspects of innate and adaptive immune responsiveness, (4) the Janus kinase-signal transducer and activator of transcription JAK-STAT) pathway essential for processes related to hematopoiesis, lactation, and immune responsiveness, (5) peroxisome proliferator-activated receptor-gamma coactivator (PGC-lα), which plays a central role in cellular metabolism and ATP production and (6) the regulation of the mitochondrial transcription factor (TFAM) and other factors essential for mitochondrial genome replication. Finally, in the mitochondria, F. PQQ and NAD+ profoundly impact oxidative metabolism, ROS control, and heat regulation through events controlled by mitochondrial sirtuins and uncoupling proteins, such as UCP2.

Figure 3

PQQ synthesis. The scheme shown for PQQ synthesis was adapted from the PQQ biosynthetic pathway in Methylobacterium extorquens. Multiple gene products (designated PqqA, PqqB, PqqC, etc.) are required for PQQ synthesis. PQQ synthesis is unusual in that PQQ is derived from the enzymatic annulation of peptidyl tyrosine and glutamic acid found in PqqA. The annulation of the glutamyl and tyrosyl residues is catalyzed by PqqD and PqqE. PqqD is a novel peptide chaperone that forms a ternary complex with the radical S-adenosylmethionine-requiring protein, Pqq E. The annulation step is then followed by oxidation, tautomerization, and the eventual proteolytic release of PQQ [36].

Figure 4

Growth and appearance of PQQ-deprived and -supplemented BALB/c mice. (A,B) are typical of a PQQ-deprived mouse and control mouse, respectively. Mice fed chemically defined diets devoid of PQQ grow poorly. Severely affected mice have friable skin, hair loss, and a kyphotic appearance. The graph indicates the growth of first-generation mouse pups born from BALB/c dams fed diets containing varying amounts of PQQ. The data suggests that a maternal and subsequent neonatal intake of approximately 300 ng PQQ/g of diet is required for optimal neonatal growth. Values are the means for a minimum of ten 6-week-old mice per. group. Additional details may be found in Steinberg et al. [60,61].

Figure 5

PQQ derivatives. PQQ can tautomerize under acidic conditions to form lactones (B), lactams (A) and hemiketals (C). In addition, PQQ readily engages in nucleophilic additions and substitutions.

Figure 6

Imidazolopyrroloquinoline (IPQ). PQQ reacts with non−branched chain amino acids to form imidazole derivatives (IPQ), with or without retention of the amino acid sidechain (R). The reverse reaction (IPQ → PQQ) most likely results from a base-catalyzed opening of the imidazolium ring as a first step (1). Next, two intermediate forms are possible with the release of the imidazole carbon atom as an aldehyde moiety with or without an attached R group (2). Finally, there is a loss of the imine function that results from nucleophilic addition of OH⁻, isomerization and oxidation (3).

Figure 7

PQQ-associated changes in the gut microbiota of offspring of obese mouse dams. Obesity in dams was induced by feeding a chow (CH) or Western-style diet (WD), with and without PQQ supplementation. Bacterial compositional differences were measured using 16S sequencing of offspring cecal contents at postnatal day 21 [107]. (A) The ratio of Bacteroidetes to Firmicutes was diminished by WD exposure and rescued by PQQ. (B) WD exposure altered relative abundances of the 13 most abundant genera, some of which returned to near control levels in offspring exposed to maternal PQQ.