Abstract
Arising from: T. Kasahara & T. Kato Nature 422, 832 (2003); see also communication from Rucker et al.; Kasahara et al. reply The announcement by Kasahara and Kato of a new redox-cofactor vitamin for mammals1, pyrroloquinoline quinone (PQQ), was based on their claim that an enzyme, predicted to be involved in mouse lysine metabolism, is a PQQ-dependent dehydrogenase. However, this claim was dependent on a sequence analysis using databases that inappropriately label β-propeller sequences as PQQ-binding motifs. What the evidence actually suggests is that the enzyme is an interesting novel protein that has a seven-bladed β-propeller structure, but there is nothing to indicate that it is a PQQ-dependent dehydrogenase.
Similar content being viewed by others
Main
In bacteria, PQQ is an essential cofactor for various dehydrogenase enzymes known as quinoproteins2. Nutritional experiments have indicated some (unknown) metabolic or nutritional role for PQQ in mammals1,3,4, but it cannot be accepted as a vitamin until it is proved to be required by an enzyme as an essential cofactor; this is the key evidence that Kasahara and Kato1 claim to have provided. In the course of a study on bipolar disorder (see http://www.brain.riken.go.jp/labs/mdmd/pqq/index-e.html), these authors cloned a mouse gene encoding a protein (U26) with some similarity to yeast aminoadipate reductase (LYS2)5; they proposed that mouse U26 could be involved in one of the important first steps in the degradation of dietary lysine, acting as a PQQ-dependent adipic 6-semialdehyde dehydrogenase.
As would be expected from the method used by Kasahara and Kato in searching for the LYS2 analogue1, the U26 sequence contained no carboxy-terminal NAD(P)-binding domain. They noted from sequence analysis that U26 has an alternative carboxy-terminal domain that contains seven repeats of the ‘PQQ-binding motif’ that is conserved among bacterial PQQ-dependent dehydrogenase enzymes, leading to the conclusion that mouse U26 could be a PQQ-dependent dehydrogenase.
However, this conclusion is based on the misconception that the Smart and Pfam databases are able to recognize PQQ-binding sites even when, as in this case, there is negligible sequence similarity to known PQQ-dependent enzymes. The ‘sites’ wrongly identified by the databases do not represent PQQ-binding sites but represent the β-sheets that form the ‘blades’ of the ‘propeller fold’ that happens to be a feature of all PQQ-dependent dehydrogenases, whose main structure is a superbarrel made up of either six or eight ‘propeller blades’ (Fig. 1). The propeller fold is not related in any direct way to PQQ binding2,6, and these folds are found in many other types of protein, which have extreme functional and phylogenetic diversity7.
We contend that there is still no compelling evidence for a PQQ-dependent enzyme in the mouse and that the authors' announcement of a new vitamin was therefore premature.
References
Kasahara, T. & Kato, T. Nature 422, 832 (2003).
Goodwin, P. M. & Anthony, C. Adv. Microb. Physiol. 40, 1–80 (1998).
McIntire, W. S. Annu. Rev. Nutr. 18, 145–177 (1998).
Steinberg, F. et al. Exp. Biol. Med. 228, 160–166 (2003).
Ehmann, D. E., Gehring, A. M. & Walsh, C. T. Biochemistry 38, 6171–6177 (1999).
Anthony, C. & Ghosh, M. Progr. Biophys. Mol. Biol. 69, 1–21 (1998).
Paoli, M. Progr. Biophys. Mol. Biol. 76, 103–130 (2001).
Author information
Authors and Affiliations
Corresponding author
Additional information
Reply: T. Kasahara and T. Kato reply to this communication (doi:10.1038/nature03324).
Rights and permissions
About this article
Cite this article
Felton, L., Anthony, C. Role of PQQ as a mammalian enzyme cofactor?. Nature 433, E10 (2005). https://doi.org/10.1038/nature03322
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature03322
This article is cited by
-
Carbon nanomaterial-based membranes in solid-phase extraction
Microchimica Acta (2023)
-
Health monitoring of composite pressure vessels through omnidirectional buckypaper sensor array
Applied Physics A (2022)
-
Pyrroloquinoline quinone promotes mitochondrial biogenesis in rotenone-induced Parkinson’s disease model via AMPK activation
Acta Pharmacologica Sinica (2021)
-
Comparative genomics and analysis of the mechanism of PQQ overproduction in Methylobacterium
World Journal of Microbiology and Biotechnology (2021)
-
Identification of lactate dehydrogenase as a mammalian pyrroloquinoline quinone (PQQ)-binding protein
Scientific Reports (2016)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.