PQQ is the first new vitamin in 55 years

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April 24, 2003
  

In a communication published in the April 24, 2003, issue of the journal Nature, we identified an organic molecules called pyrroloquinoline quinone (PQQ) as a new vitamin for mammals. Vitamins are essential nutritions, which assist specific enzyme(s) in our body. Since the first vitamin (now called vitamin B1) was discovered in 1910 by Dr. U. Suzuki, thirteen substances have been recognized as vitamins; the latest one was vitamin B12 found in 1948. PQQ was discovered in 1979 from a bacterium, and afterward it was reported to be in common foods. Because PQQ-deprived mice showed several abnormalities, such as poor development and breakable skin, PQQ has been considered as a candidate for vitamin. It was a mystery, however, with what enzyme PQQ is connected, preventing PQQ from being recognized as a vitamin. In this study, we discovered a mammalian PQQ-linked enzyme. The enzyme was involved in the degradation of the amino acid lysine, and it required PQQ to function normally. This brand-new vitamin will be also important for humans, and we are hoping for a great contribution in medical fields.



Background
Pyrroloquinoline quinone (PQQ; Fig.1) is an organic molecule found from bacteria as a reduction-oxidization (redox) cofactor[*1], such as nicotinamides (pyridine nucleotides) and flavins. Because mice fed a PQQ-deficient diet showed several abnormalities; they grew slowly, had fragile skin, and showed poor reproductive performance, PQQ was thought to be one of the important nutrients for mammals. However, the biochemical role was unknown.
In the course of the study on bipolar disorder (manic depression), we cloned a novel gene, which was related to the metabolism of lysine, an essential amino acid. Lysine is degraded mainly to 2-aminoadipic 6-semialdehyde (AAS) and subsequently oxidized to 2-aminoadipic acid (AAA) (Fig.2). The gene for AAS dehydrogenase catalyzing the oxidation of AAS to AAA has not been found until now. The discovery of the gene led us to identify the new vitamin PQQ.

[Fig.1] Chemical structure of PQQ
[Fig.2] Initial steps of lysine degradation
Lysine is oxidized to aminoadipic semialdehyde (AAS) catalyzed by AAS synthetase (AASS), and then oxidized furthermore by AAS dehydrogenase (AASDH). In the second step, PQQ functions as a redox cofactor.

PQQ-linked enzyme "AAS dehydrogenase"
Based on the the primary structure of the protein that was guessed from the cloned gene, in the latter half (C-terminal) part of the AAS dehydrogenase there exist seven repeats of "PQQ-binding motif" (Fig.3). The PQQ-binding motif is commonly found in bacterial PQQ-dependent dehydrogenases. The six to eight tandem repeats of the motif are also present in these PQQ-dependent dehydrogenases, indicating that mouse AAS dehydrogenase could be a PQQ-dependent enzyme. From afterwards analysis, it was proven that the gene for AAS dehydrogenase are widely present not only in mammals such as human but also in other vertebrates, invertebrates, and higher plants such as rice.

[Fig.3] Arrangement of putative domains in AAS dehydrogenase
Murine AAS dehydrogenase is a protein of 1,100 amino acids. There is a structure (pink) for combining with the substrate in the N-terminal side and seven repeats of PQQ-binding motif (blue) in the C-terminal side.

PQQ-deprived mice
We examined the effects of a PQQ-deficient diet on mice to see the importance of PQQ in the lysine degradation pathway. As reported, several abnormalities were observed in PQQ-deprived mice; the reproductive performance was low and the lie of fur was bad. We measured the blood levels of lysine and AAA, and found that AAA concentration was significantly decreased in PQQ-deprived mice. This decrease in AAA may be indicative of impaired AAS dehydrogenase, suggesting a requirement for PQQ as a redox cofactor for the proper functioning of AAS dehydrogenase.


PQQ is a new vitamin
Our current results clarifing the biochemical role of PQQ seem to determine for the first time that PQQ is a vitamin for animals. Humans must take nicotinamides and flavins, already-known redox cofactors, from outer sources as vitamin B3 (niacin) and vitamin B2 (riboflavin), respectively. PQQ may also be considered a member of the vitamin B group[*2] by its molecular nature[*3] and function. PQQ is mostly contained in common foods; comparatively in large quantities in natto (fermented soybeans), tea, papayas, and kiwi fruits (Table 1). At present, PQQ is not added to medical vitamin tablets (oral agent and parenteral injection) and multi-vitamin supplements. Although it is uncertain whether there are PQQ-depleted humans, PQQ will apply to various scenes as a vitamin.


Please also see FAQs about PQQ.

[*1] Redox cofactor
Many oxidation-reduction enzymes bind with organic molecules, which assist the reactions, and they are called redox cofactors. Proteins consisting of only amino acids cannot catalyze oxidation-reduction reactions.

[*2] Vitamin B group
Historically, a water-soluble material, which was indispensable for the development of rats, was called vitamin B. But, multiple compounds with various actions were isolated from it, and it was called a vitamin B complex. The compounds isolated from the complex belong to vitamin B group. Concretely, the following are included: thiamine (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6), folic acid, biotin, and cobalamin (B12). Though PQQ might be included in the vitamin B complex, there is no data showing it. Because vitamins are tend to be called in the material names, PQQ should be called in the same way as folic acid and biotin.

[*3] Molecular nature of PQQ
Because there are three carboxyl groups, PQQ is a water-soluble compound. It has a quinone skeleton as well as vitamin B2 (riboflavin) (the lower right side of Fig.1), and the part of left side contains a similar chemical property to that of vitamin B6.



[Table 1] Concentrations of PQQ in various foods




[Table 2] List of the widely-accepted vitamins