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The ins and outs of biological zinc sites

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Abstract

The inner shell coordination properties of zinc proteins have led to the identification of four types of zinc binding sites: catalytic, cocatalytic, structural, and protein interface. Outer shell coordination can influence the stability of the zinc site and its function as exemplified herein by the zinc sites in carbonic anhydrase, promatrix metalloproteases and alcohol dehydrogenase. Agents that disrupt these interactions, can lead to increased off rate constants for zinc. d-penicillamine is the first drug to inhibit a zinc protease by catalyzing the removal of the metal. Since it can accept the released zinc we have referred to it as a catalytic chelator. Agents that catalyze the release of the metal in the presence of a scavenger chelator will also inhibit enzyme catalysis and are referred to as enhanced dechelation inhibitors.

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References

  • Andreini C, Banci L, Bertini I, Rosato A (2006a) Counting the zinc-proteins encoded in the human genome. J Proteome Res 5:196–201. doi:10.1021/pr050361j

    Article  PubMed  CAS  Google Scholar 

  • Andreini C, Banci L, Bertini I, Rosato A (2006b) Zinc through the three domains of life. J Proteome Res 5:3173–3178. doi:10.1021/pr0603699

    Article  PubMed  CAS  Google Scholar 

  • Argos P, Garavito RM, Eventoff W, Rossmann MG, Branden CI (1978) Similarities in active center geometries of zinc-containing enzymes, proteases and dehydrogenases. J Mol Biol 126:141–158. doi:10.1016/0022-2836(78)90356-X

    Article  PubMed  CAS  Google Scholar 

  • Auld DS (1988) Use of chelating agents to inhibit enzymes. Methods Enzymol 158:110–114. doi:10.1016/0076-6879(88)58051-5

    Article  PubMed  CAS  Google Scholar 

  • Auld DS (1995) Removal and replacement of metal ions in metallopeptidases. Methods Enzymol 248:228–242. doi:10.1016/0076-6879(95)48016-1

    Article  PubMed  CAS  Google Scholar 

  • Auld DS (2001a) Zinc coordination sphere in biochemical zinc sites. Biometals 14:271–313. doi:10.1023/A:1012976615056

    Article  PubMed  CAS  Google Scholar 

  • Auld DS (2001b) Zinc sites in metalloenzymes and related proteins. In: Bertini I, Sigel A, Sigel H (eds) Handbook on metalloproteins. M. Dekker, New York, pp 881–959

    Google Scholar 

  • Auld DS (2004a) Cocatalytic zinc sites. In: Messerschmidt A, Bode W, Cygler M (eds) The handbook of metalloproteins. Wiley, Chichester, pp 416–431

    Google Scholar 

  • Auld DS (2004b) Structural zinc sites. In: Messerschmidt A, Bode W, Cygler M (eds) The handbook of metalloproteins. Wiley, Chichester, pp 403–415

    Google Scholar 

  • Auld DS (2005) Zinc Enzymes. In: King RB (ed) Encyclopedia of inorganic chemistry. Wiley, Chichester, pp 5885–5927

    Google Scholar 

  • Auld DS, Bergman T (2008) Medium- and short-chain dehydrogenase/reductase gene and protein families: the role of zinc for alcohol dehydrogenase structure and function. Cell Mol Life Sci 65:3961–3970. doi:10.1007/s00018-008-8593-1

    Article  PubMed  CAS  Google Scholar 

  • Bergman T, Zhang K, Palmberg C, Jörnvall H, Auld DS (2008) Zinc binding to peptide Analogs of the structural zinc site in alcohol dehydrogenase: implications for an entatic state. Cell Mol Life Sci 65:4019–4027. doi:10.1007/s00018-008-8379-5

    Article  PubMed  CAS  Google Scholar 

  • Chong CR, Auld DS (2000) Inhibition of carboxypeptidase A by d-pencillamine: mechanism and implications for drug design. Biochemistry 39:7580–7588. doi:10.1021/bi000101+

    Article  PubMed  CAS  Google Scholar 

  • Chong CR, Auld DS (2007) Catalysis of zinc transfer by d-penicillamine to secondary chelators. J Med Chem 50:5524–5527. doi:10.1021/jm070803y

    Article  PubMed  CAS  Google Scholar 

  • Christianson DW, Fierke CA (1996) Carbonic anhydrase: evolution of the design of the zinc binding site by nature and by design. Acc Chem Res 29:331–339. doi:10.1021/ar9501232

    Article  CAS  Google Scholar 

  • Eklund H, Nordstrom B, Zeppezauer E, Soderlund G, Ohlsson I, Boiwe T, Soderberg BO, Tapia O, Branden CI, Akeson A (1976) Three-dimensional structure of horse liver alcohol dehydrogenase at 2–4 A resolution. J Mol Biol 102:27–59. doi:10.1016/0022-2836(76)90072-3

    Article  PubMed  CAS  Google Scholar 

  • Jozic D, Bourenkov G, Lim NH, Visse R, Nagase H, Bode W, Maskos K (2005) X-ray structure of human proMMP-1: new insights into procollagenase activation and collagen binding. J Biol Chem 280:9578–9585. doi:10.1074/jbc.M411084200

    Article  PubMed  CAS  Google Scholar 

  • Kagi JH, Schaffer A (1988) Biochemistry of metallothionein. Biochemistry 27:8509–8515. doi:10.1021/bi00423a001

    Article  PubMed  CAS  Google Scholar 

  • Kiefer LL, Paterno SA, Fierke CA (1995) Hydrogen bond network in the metal binding site of carbonic anhydrase enhances zinc affinity and catalytic efficiency. J Am Chem Soc 117:6831–6837. doi:10.1021/ja00131a004

    Article  CAS  Google Scholar 

  • Krezel A, Maret W (2007) Different redox states of metallothionein/thionein in biological tissue. Biochem J 402:551–558. doi:10.1042/BJ20061044

    Article  PubMed  CAS  Google Scholar 

  • Lesburg CA, Christianson DW (1995) X-ray crystallographic studies of engineered hydrogen bond networks in a protein–zinc binding site. J Am Chem Soc 117:6838–6844. doi:10.1021/ja00131a005

    Article  CAS  Google Scholar 

  • Maret W (2004) Protein interface zinc sites: the role of zinc in the supramolecular assembly of proteins and in transient protein–protein interactions. In: Messerschmidt A, Bode W, Cygler M (eds) The handbook of metalloproteins. Wiley, Chichester, pp 432–441

    Google Scholar 

  • Morgunova E, Tuuttila A, Bergmann U, Isupov M, Lindqvist Y, Schneider G, Tryggvason K (1999) Structure of human pro-matrix metalloproteinase-2: activation mechanism revealed. Science 284:1667–1670. doi:10.1126/science.284.5420.1667 (see comments)

    Article  PubMed  CAS  Google Scholar 

  • Natesh R, Schwager SL, Sturrock ED, Acharya KR (2003) Crystal structure of the human angiotensin-converting enzyme–lisinopril complex. Nature 421:551–554. doi:10.1038/nature01370

    Article  PubMed  CAS  Google Scholar 

  • Ondetti MA, Rubin B, Cushman DW (1977) Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents. Science 196:441–444. doi:10.1126/science.191908

    Article  PubMed  CAS  Google Scholar 

  • Patel K, Kumar A, Durani S (2007) Analysis of the structural consensus of the zinc coordination centers of metalloprotein structures. Biochim Biophys Acta 1774:1247–1253

    PubMed  CAS  Google Scholar 

  • Prasad AS, Schulert AR, Miale A Jr, Farid Z, Sandstead HH (1963) Zinc and iron deficiencies in male subjects with dwarfism and hypogonadism but without ancylostomiasis, schistosomiasis or severe anemia. Am J Clin Nutr 12:437–444

    PubMed  CAS  Google Scholar 

  • Raulin J (1869) Etudes cliniques sur la vegetation. Ann Sci Bot Biol Veg 11:93

    Google Scholar 

  • Sillen LG, Martell AE (1971) Stability constants of metal–ion complexes. The Chemical Society, London, pp 250–281

    Google Scholar 

  • Springman EB, Angleton EL, Birkedal-Hansen H, Van Wart HE (1990) Multiple modes of activation of latent human fibroblast collagenase: evidence for the role of a Cys73 active-site zinc complex in latency and a “cysteine switch” mechanism for activation. Proc Natl Acad Sci USA 87:364–368. doi:10.1073/pnas.87.1.364

    Article  PubMed  CAS  Google Scholar 

  • Towler P, Staker B, Prasad SG, Menon S, Tang J, Parsons T, Ryan D, Fisher M, Williams D, Dales NA, Patane MA, Pantoliano MW (2004) ACE2 structures reveal a large hinge-bending motion important for inhibitor binding and catalysis. J Biol Chem 279:17996–18007. doi:10.1074/jbc.M311191200

    Article  PubMed  CAS  Google Scholar 

  • Vallee BL, Auld DS (1990a) Active-site zinc ligands and activated H2O of zinc enzymes. Proc Natl Acad Sci USA 87:220–224. doi:10.1073/pnas.87.1.220

    Article  PubMed  CAS  Google Scholar 

  • Vallee BL, Auld DS (1990b) Zinc coordination, function, and structure of zinc enzymes and other proteins. Biochemistry 29:5647–5659. doi:10.1021/bi00476a001

    Article  PubMed  CAS  Google Scholar 

  • Vallee BL, Auld DS (1993) New perspective on zinc biochemistry: cocatalytic sites in multi-zinc enzymes. Biochemistry 32:6493–6500. doi:10.1021/bi00077a001

    Article  PubMed  CAS  Google Scholar 

  • Vasak M, Kagi JHR (1983) Spectroscopic properties of metallothionein. Metal Ions Biol Syst 16:213–273

    Google Scholar 

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  1. Department of Biology, Boston College, Chestnut Hill, Boston, MA, 02467, USA

    David S. Auld

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Auld, D.S. The ins and outs of biological zinc sites. Biometals 22, 141–148 (2009). https://doi.org/10.1007/s10534-008-9184-1

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