Quinone Cofactors

Abstract

Quinone cofactors are used by several classes of enzymes, which catalyse the oxidation of biogenic amines and alcohols, to help catalyse these reactions. Before 1990 only one cofactor, the peptide‐derived pyrroloquinoline quinone had been identified. During 1990–2001, however, four new quinone prosthetic groups derived from naturally occurring amino acids were discovered. The first protein‐derived, nondissociable cofactor identified was 2,4,5‐trihydroxyphenylalanine quinone, designated topaquinone (TPQ) in copper amine oxidases. The discovery of TPQ led to the identification of a series of new quinone cofactors, including lysine tyrosylquinone (LTQ) in lysyl oxidase, cysteine tryptophylquinone (CTQ) in quinohaemoprotein amine dehydrogenase and tryptophan tryptophylquinone (TTQ) in bacterial methylamine dehydrogenase. These cofactors contribute electrophillic capabilities (and stabilise free radical intermediates) that naturally occurring, unmodified amino acid side chains are unable to provide.

Key Concepts:

  • Quinone cofactors are a class of cofactors used by many enzymes to catalyse the oxidation of amines and alcohols.

  • Five quinone cofactors have been characterised: PQQ, TPQ, LTQ, TTQ and CTQ.

  • PQQ is a peptide‐derived cofactor that involves the expression of six genes located within an operon.

  • TPQ is derived from a precursor tyrosine and requires only Cu2+ and O2 for biogenesis.

  • LTQ is formed by the cross‐linking of a tyrosine residue and a lysine residue, also requiring only Cu2+ and O2.

  • TTQ is formed by the cross‐linking of two tryprophan resides, with MauG completing biogenesis.

  • CTQ, the most recently discovered quinone cofactor, is formed by the cross‐linking of a cysteine reside and a tryptophan residue.

Keywords: structure and function; catalytic mechanisms; biogenesis; model compounds

Figure 1.

Structures of quinocofactors. The structures of topaquinone (TPQ), lysine tyrosylquinone (LTQ), tryptophan tryptophylquinone (TTQ), cysteine tryptophylquinone (CTQ) and pyrroloquinoline quinone (PQQ) are shown.

Figure 2.

Working mechanism for the generation of TPQ from its tyrosine precursor in HPAO (Dove et al., ; Schwartz et al., ).

Figure 3.

Simulated annealing omit map for a new active site structure observed during biogenesis of HPAO Y305F expressed in E. coli. Reprinted with permission from Chen et al., . © 2010 American Chemical Society.

Figure 4.

(a) Postulated mechanism for the branching of a biogenesis intermediate to TPQ and TPO. (b) Model to explain 3,4‐dihydroperoxo‐prouct. (c) Model to explain 2,4‐dihydroperoxo‐product. Reprinted with permission from Chen et al., . © 2010 American Chemical Society.

Figure 5.

Proposed catalytic mechanism of the CAO from H. polymorpha (Mure et al., ). In CAOs from other sources, it is proposed that the reduced aminophenol first reduces Cu2+ to Cu1+, which then reacts with O2 to yield the Cu2+ (Dooley et al., ).

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References

Anthony C (2001) Pyrroloquinoline quinone (PQQ) and quinoprotein enzymes. Antioxidants and Redox Signaling 3(5): 757–774.

Anthony C (2004) The quinoprotein dehydrogenases for methanol and glucose. Archives of Biochemistry and Biophysics 428(1): 2–9.

Anthony C and Williams P (2003) The structure and mechanism of methanol dehydrogenase. Biochimica et Biophysica Acta 1647(1–2): 18–23.

Bollinger JA, Brown DE and Dooley DM (2005) The formation of lysine tyrosylquinone (LTQ) is a self‐processing reaction. Expression and characterization of a Drosophila lysyl oxidase. Biochemistry 44(35): 11708–11714.

Boomsma F, de Kam PJ, Tjeerdsma G, Van Den Meiracker HA and Van Veldhuisen DJ (2000) Plasma semicarbazide‐sensitive amine oxidase (SSAO) is an independent prognostic marker for mortality in chronic heart failure. European Heart Journal 21(22): 1859–1863.

Boomsma F, van den Meiracker AH, Winkel S et al. (1999) Circulating semicarbazide‐sensitive amine oxidase is raised both in type I (insulin‐dependent), in type II (non‐insulin‐dependent) diabetes mellitus and even in childhood type I diabetes at first clinical diagnosis. Diabetologia 42(2): 233–237.

Chen L, Durley RC, Mathews FS and Davidson VL (1994) Structure of an electron transfer complex: methylamine dehydrogenase, amicyanin, and cytochrome c551i. Science 264(5155): 86–90.

Chen ZW, Datta S, Dubois JL, Klinman JP and Mathews FS (2010) Mutation of a strictly conserved, active site tyrosine in the copper amine oxidase leads to uncontrolled oxygenase activity. Biochemistry 49(34): 7393–7402.

Datta S, Mori Y, Takagi K et al. (2001) Structure of a quinohemoprotein amine dehydrogenase with an uncommon redox cofactor and highly unusual crosslinking. Proceedings of the National Academy of Sciences of the USA 98(25): 14268–14273.

Dooley DM, McGuirl MA, Brown DE et al. (1991) A Cu(I)‐semiquinone state in substrate‐reduced amine oxidases. Nature 349(6306): 262–264.

Dove JE, Schwartz B, Williams NK and Klinman JP (2000) Investigation of spectroscopic intermediates during copper‐binding and TPQ formation in wild‐type and active‐site mutants of a copper‐containing amine oxiase from yeast. Biochemistry 39(13): 3690–3698.

DuBois JL and Klinman JP (2005) Mechanism of post‐translational quinone formation in copper amine oxidases and its relationship to the catalytic turnover. Archives of Biochemistry and Biophysics 433(1): 255–265.

DuBois JL and Klinman JP (2006) Role of a strictly conserved active site tyrosine in cofactor genesis in the copper amine oxidase from Hansenula polymorpha. Biochemistry 45(10): 3178–3188.

Duine JA (1999) The PQQ story. Journal of Bioscience and Bioengineering 88(3): 231–236.

Duine JA (2001) Cofactor diversity in biological oxidation; implications and applications. Chemical Record 1(1): 74–83.

Fujieda N, Mori M, Kano K and Ikeda T (2002) Spectroelectrochemical evaluation of redox potentials of cysteine tryptophylquinone and two hemes c in quinohemoprotein amine dehydrogenase from Paracoccus denitrificans. Biochemistry 41(46): 13736–13743.

Gacheru SN, Trackman PC, Shah MA et al. (1990) Structural and catalytic properties of copper in lysyl oxidase. Journal of Biological Chemistry 265(31): 19022–19027.

Goodwin PM and Anthony C (1998) The biochemistry, physiology and genetics of PQQ and PQQ‐containing enzyme. Advances in Microbial Physiology 40: 1–80.

Goosen N, Horsman HPA, Huinen RGM and van de Putte P (1989) Acinetobacter calcoaceticus genes involved in biosynthesis of the coenzyme pyrrolo‐quinoline‐quinone: nucleotide sequence and expression in Escherichia coli K‐12. Journal of Bacteriology 171(1): 447–455.

Grant KL and Klinman JP (1989) Evidence that both protium and deuterium undergo significant tunnelling in the reaction catalysed by bovine serum amine oxidase. Biochemistry 28(16): 6597–6605.

Harris TK and Davidson VL (1993) Binding and electron transfer reactions between methanol dehydrogenase and its physiologic electron acceptor cytochrome c‐551i: a kinetic and thermodynamic analysis. Biochemistry 32(51): 14145–14150.

Harris TK, Davidson VL, Chen L, Mathews FS and Xia ZX (1994) Ionic strength dependence of the reaction between methanol dehydrogenase and cytochrome c‐551i: evidence of conformationally coupled electron transfer. Biochemistry 33(42): 12600–12608.

Hartmann C and Klinman JP (1987) Reductive trapping of substrate to bovine plasma amine oxidase. Journal of Biological Chemistry 262(3): 962–965.

Hevel JM, Mills SA and Klinman JP (1999) Mutation of a strictly conserved, active‐site residue alters substrate specificity and cofactor biogenesis in a copper amine oxidase. Biochemistry 38(12): 3683–3693.

Houck DR, Hanners JL and Unkefer CJ (1988) Biosynthesis of pyrroloquinoline quinone. 1. Identification of a biosynthetic precursor using 13C labeling and NMR spectroscopy. Journal of the American Chemical Society 110(20): 6920–6921.

Houck DR, Hanners JL and Unkefer CJ (1991) Biosynthesis of pyrroloquinoline quinone. 2. Biosynthetic assembly from glutamate and tyrosine. Journal of the American Chemical Society 113(8): 3162–3166.

Itoh S, Kawakami H and Fukuzumi S (1997) Modeling of the chemistry of quinoprotein methanol dehydrogenase. Oxidation of methanol by calcium complex of coenzyme PQQ via addition‐elimination mechanism. Journal of the American Chemical Society 119(2): 439–440.

Itoh S, Ogino M, Haranou S et al. (1995) A model compound of the novel cofactor tryptophan tryptophylquinone of bacterial methylamine dehydrogenases. Synthesis and physicochemical properties. Journal of the American Chemical Society 117(5): 1485–1493.

Itoh S, Takada N, Haranou S et al. (1996) Model Studies of TTQ‐Containing Amine Dehydrogenases. Journal of Organic Chemistry 61(25): 8967–8974.

Janes SM and Klinman JP (1991) An investigation of bovine serum amine oxidase active site stoichiometry: evidence for an aminotransferase mechanism involving two carbonyl cofactors per enzyme dimer. Biochemistry 30(18): 4599–4605.

Janes SM, Mu D, Wemmer D et al. (1990) A new redox cofactor in eukaryotic enzymes: 6‐hydroxydopa at the active site of bovine serum amine oxidase. Science 248(4958): 981–987.

Klinman JP and Mu D (1994) Quinoenzymes in Biology. Annual Review of Biochemistry 63: 299–344.

Kumar V, Dooley DM, Freeman HC et al. (1996) Crystal structure of a eukaryotic (pea seedling) copper‐containing amine oxidase at 2.2 Å resolution. Structure 4(8): 943–955.

Li R, Chen L, Cai D, Klinman JP and Mathews FS (1997) Crystallographic study of yeast copper amine oxidase. Acta Crystallographica Section D 53(Pt 4): 364–370.

Lindstrom A and Pettersson G (1978) Active‐site titration of pig‐plasma benzylamine oxidase. European Journal of Biochemistry 83(1): 131–135.

Magnusson OT, Toyama H, Saeki M, Schwarzenbacher R and Klinman JP (2004) The structure of a biosynthetic intermediate of pyrroloquinoline quinone (PQQ) and elucidation of the final step of PQQ biogenesis. Journal of the American Chemical Society 126(17): 5342–5343.

Marttila‐Ichihara F, Auvinen K, Elima K, Jalkanen S and Salmi M (2009) Vascular adhesion protein‐1 enhances tumor growth by supporting recruitment of Gr‐1+CD11b+ myeloid cells into tumors. Cancer Research 69(19): 7875–7883.

McIntire WS, Wemmer DE, Chistoserdov A and Lidstrom ME (1991) A new cofactor in a prokaryotic enzyme: tryptophan tryptophylquinone as the redox prosthetic group in methylamine dehydrogenase. Science 252(5007): 817–824.

Moore RH, Spies MA, Culpepper MB et al. (2007) Trapping of a dopaquinone intermediate in the TPQ cofactor biogenesis in a copper‐containing amine oxidase from Arthrobacter globiformis. Journal of the American Chemical Society 129(37): 11524–11534.

Murakami Y, Tachi Y and Itoh S (2004) A model compound of the novel organic cofactor CTQ (cysteine tryptophylquinone) of quinohemoprotein amine dehydrogenase. European Journal of Organic Chemistry 14: 3074–3079.

Mure M and Klinman JP (1993) Synthesis and spectroscopic characterization of model compounds for the active site cofactor in copper amine oxidases. Journal of the American Chemical Society 115(16): 7117–7127.

Mure M, Mills SA and Klinman JP (2002) Catalytic mechanism of the topa quinone containing copper amine oxidases. Biochemistry 41(30): 9269–9278.

Murray JM, Saysell CG, Wilmot CM et al. (1999) The active site base controls reactivity in E. coli amine oxidase: X‐ray crystallographic studies with mutational variants. Biochemistry 38(26): 8217–8227.

Nagel ZD and Klinman JP (2010) Update 1 of: tunneling and dynamics in enzymatic hydride transfer. Chemical Reviews 110(12): PR41–PR67.

Ono K, Okajima T, Tani M et al. (2006) Involvement of a putative [Fe‐S]‐cluster‐binding protein in the biogenesis of quinohemoprotein amine dehydrogenase. Journal of Biological Chemistry 281(19): 13672–13684.

Salmi M and Jalkanen S (1992) A 90‐kilodalton endothelial cell molecule mediating lymphocyte binding in humans. Science 257(5075): 1407–1409.

Schwartz B, Dove JE and Klinman JP (2000) Kinetic analysis of oxygen utilization during cofactor biogenesis in a copper‐containing amine oxidase from yeast. Biochemstry 39(13): 3699–3707.

Shah MA, Scaman CH, Palcic MM and Kagan HM (1993) Kinetics and stereospecificity of the lysyl oxidase reaction. Journal of Biological Chemistry 268(16): 11573–11579.

Shen SH, Wertz DL and Klinman JP (2012) Implication for functions of the ectopic adipocyte copper amine oxidase (AOC3) from purified enzyme and cell‐based kinetic studies. PLoS One 7(1): e29270.

Toyama H, Chistoserdova L and Lidstrom ME (1997) Sequence analysis of pqq genes required for biosynthesis of pyrroloquinoline quinone in Methylobacterium extorquens AM1 and the purification of a biosynthetic intermediate. Microbiology 143(Pt2): 595–602.

Toyama H, Fukumoto J, Saeki M et al. (2002) PqqC/D, which converts a biosynthetic intermediate to pyrroloquinoline quinone. Biochemical and Biophysical Research Communications 299(2): 268–272.

Tsai TY, Yang CY, Shih HL, Wang AH and Chou SH (2009) Xanthomonas campestris PqqD in the pyrroloquinoline quinone biosynthesis operon adopts a novel saddle‐like fold that possibly serves as a PQQ carrier. Proteins 76(4): 1042–1048.

Veletrop JS, Sellink E, Meulenberg JJM et al. (1995) Synthesis of pyrroloquinoline quinone in vivo and in vitro and detection of an intermediate in the biosynthetic pathway. Journal of Bacteriology 177(17): 5088–5098.

Wang SX, Mure M, Medzihradszky KF et al. (1996) A crosslinked cofactor in lysyl oxidase: redox function for amino acid side chains. Science 273(5278): 1078–1084.

Wang Y, Graichen ME, Liu A et al. (2003) MauG, a novel diheme protein required for tryptophan tryptophylquinone biogenesis. Biochemistry 42(24): 7318–7325.

Wecksler SR, Stoll S, Iavarone AT et al. (2010) Interaction of PqqE and PqqD in the pyrroloquinoline quinone (PQQ) biosynthetic pathway links PqqD to the radical SAM superfamily. Chemical Communications (Cambridge) 46(37): 7031–7033.

Wecksler SR, Stoll S, Tran H et al. (2009) Pyrroloquinoline quinone biogenesis: demonstration that PqqE from Klebsiella pneumoniae is a radical S‐Adenosyl‐l‐methionine enzyme. Biochemistry 48(42): 10151–10161.

White S, Boyd G, Mathews FS et al. (1993) The active site structure of the calcium‐containing quinoprotein methanol dehydrogenase. Biochemistry 32(48): 12955–12958.

Wilce MCJ, Dooley DM, Freeman HC et al. (1997) Crystal structures of the copper‐containing amine oxidase from Arthrobacter globiformis in the holo and apo forms: implications for the biogenesis of topaquinone. Biochemistry 36(51): 16116–16133.

Williamson PR and Kagan HM (1986) Reaction pathway of bovine aortic lysyl oxidase. Journal of Biological Chemistry 261(20): 9477–9482.

Wilmot CM and Davidson VL (2009) Uncovering novel biochemistry in the mechanism of tryptophan tryptophylquinone cofactor biosynthesis. Current Opinion in Chemical Biology 13(4): 469–474.

Wilmot CM, Murray JM, Alton G et al. (1997) Catalytic mechanism of the quinoenzyme from E. coli: exploring the reductive half‐reduction. Biochemistry 36(7): 1608–1620.

Further Reading

Anthony C (1996) Quinoprotein‐catalysed reactions. Biochemical Journal 320(Pt3): 697–711.

Davidson VL (2007) Protein‐derived cofactors. Expanding the scope of post‐translational modifications. Biochemistry 46(18): 5283–5292.

Davidson VL (ed.) (1993) Principles and Applications of Quinoproteins. New York: Marcel Dekker.

Klinman JP (1996) New quinocofactors in eukaryotes. Journal of Biological Chemistry 271(44): 27189–27192.

Klinman JP (2003) The multi‐functional topa‐quinone copper amine oxidases. Biochimica et Biophysica Acta 1647(1‐2): 131–137.

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Lang, Albert, and Klinman, Judith P(Feb 2013) Quinone Cofactors. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000660.pub2]