Antibiotic Biosynthetic Enzymes (ABE)
>Current research in biochemistry
Contact
Email jarnie [at] utu.fi
Phone +358-2-333 6877
Antibiotic Biosynthetic Enzymes homepage
Members
Professor Emeritus Pekka Mäntsälä (Project Leader)
Lecturer Jarmo Niemi, Ph.D. (Project Leader)
Senior Research Fellow Mikko Metsä-Ketelä, Ph.D. (Project Leader)
Postdoctoral Researcher Laila Niiranen, Ph.D.
Ph.D. students Thadée Grocholski, M.Sc./ Terhi Oja, M.Sc./ Vilja Siitonen, M.Sc./ Pekka Patrikainen, M.Sc.
Pro gradu students Pasi Paananen / Linnea Samila
Background
Members of the bacterial genus Streptomyces are undisputedly amongst the most versatile producers of bioactive secondary metabolites found in nature. In addition to a wide range of compounds used in human therapeutics and veterinary medicine, Streptomyces-derived metabolites continue to uphold a central role in the development of new pharmacologically active compounds and novel drug leads. One of the most intensively studied chemical entities produced by different Streptomyces species is the diverse group of polyketide compounds. Examples of these include avermectin, doxorubicin, rapamycin and tetracycline currently in commercial use.
The biosynthetic potential behind the Streptomyces’ metabolic diversity is of great scientific and commercial interest, and embraces multidisciplinary research in different fields of medicine and bioscience world-wide. [See ABE homepage for more extensive background]
Research
Our research is centered around the enzymology of Type II aromatic polyketide biosynthesis in Streptomyces bacteria. We are focused on the post-PKS modification reactions in several anthracycline, angucycline and benzoisochromane quinone (BIQ) pathways. The aim is to gain detailed molecular-level information on the enzymatic reactions, the catalytic mechanisms and the interactions involved. Our areas of expertise range from genetic molecular biology and related Streptomyces in vivo applications to in vitro enzyme chemistry, enzyme structural biology, and natural product chemistry.
ABE is primarily funded by The Academy of Finland & ISB graduate school
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Publications
List of publications with direct .pdf links Patrikainen, P., Kallio, P., Fan, K., Klika, K.D., Shaaban, K.A., Mäntsälä, P., Rohr, J., Yang, K., Niemi, J. and Metsä-Ketelä. M. (2012) Tailoring Enzymes Involved in the Biosynthesis of Angucyclines Contain Latent Context-Dependent Catalytic Activities. Accepted for publication in Chemistry & Biology April 2012.
Siitonen, V., Blauenburg, B., Kallio, P., Mäntsälä, P. and Metsä-Ketelä, M. (2012) Discovery of a Novel Two-Component Monooxygenase SnoaW/SnoaL2 Involved in Nogalamycin Biosynthesis. Accepted for publication in Chemistry & Biology April 2012.
Thadée Grocholski, Terhi Oja, Laurence Humphrey, Pekka Mäntsälä, Jarmo Niemi, and Mikko Metsä-Ketelä. Characterization of the two-component monooxygenase system AlnT/AlnHreveals early timing of quinone formation in alnumycin biosynthesis. J. Bacteriol. published ahead of print 30 March 2012 , doi:10.1128/JB.00228-12
Terhi Oja, Karel D. Klika, Laura Appassamy, Jari Sinkkonen, Pekka Mäntsälä, Jarmo Niemi, and Mikko Metsä-Ketelä. Biosynthetic pathway toward carbohydrate-like moieties of alnumycins contains unusual steps for C-C bond formation and cleavage. PNAS 2012 ; published ahead of print April 2, 2012, doi:10.1073/pnas.1201530109
Epimers vs. inverse epimers: the C-1 configuration in alnumycin A1. Petri Tähtinen, Terhi Oja, Nadine Deiack, Pekka Mäntsälä, Jarmo Niemi, Mikko Metsä-Ketelä and Karel D Klika. RSC Adv., 2012, Accepted Manuscript DOI: 10.1039/C2RA20537H, Communication
Siitonen, V., Claesson, M., Patrikainen, P., Aromaa, M., Mäntsälä, P., Schneider, G., and Metsä-Ketelä, M (2012) Identification of late-stage glycosylation steps on the biosynthetic pathway of the anthracycline nogalamycin. ChemBioChem 13 (1): 120-128.
Kallio, P., Patrikainen, P., Suomela, J-P., Mäntsälä, P., Metsä-Ketelä, M. and Niemi, J. (2011) Flavoprotein Hydroxylase PgaE Catalyses Two Consecutive Oxygen-Dependent Tailoring Reactions in Angucycline Biosynthesis. Biochemistry, 50(24):5535-5543.
Grocholski, T., Koskiniemi, H., Lindqvist, Y., Mäntsälä, P., Niemi, J. and Schneider, G. (2010) Crystal structure of the cofactor-independent monooxygenase SnoaB from Streptomyces nogalater: implications for the reaction mechanism. Biochemistry 49(5): 934-944.
Liljeblad, A., Kallio, P., Vainio, M., Niemi, J. and Kanerva, L. T. (2010) Formation and hydrolysis of amide bonds by lipase A from Candida antarctica; exceptional features. Org. Biomol. Chem. 8: 886-895.
Lindqvist, Y., Koskiniemi, H., Jansson, A., Sandalova, T., Schnell, R., Liu, Z., Mäntsälä, P.,Niemi, J., and Schneider, G. (2009) Structural basis for substrate recognition and specificity in aklavinone-11-hydroxylase from rhodomycin biosynthesis. J. Mol. Biol. 393(4): 966-977.
Koskiniemi, H., Grocholski, T., Schneider, G., and Niemi, J. (2009) Expression, purification and crystallization of the cofactor-independent monooxygenase SnoaB from the nogalamycin biosynthetic pathway. Acta Crystallogr. Section F. F65: 256-259.
Xu Z., Metsä-Ketelä M. and Hertweck C. (2008) Ketosynthase III as a gateway to engineering the biosynthesis of antitumoral benastatin derivatives. J. Biotechnol. 140: 107-113.
Kallio, P. (2008) Type II aromatic polyketide biosynthetic tailoring enzymes: diversity and adaptation in Streptomyces secondary metabolism. Annales Universitatis Turkuensis A I 386 (doctoral thesis).
Oja, T., Palmu, K., Lehmussola, H., Leppäranta, O., Hännikäinen, K., Niemi, J., Mäntsälä, P. and Metsä-Ketelä, P. (2008) Characterization of the Alnumycin Gene Cluster Reveals Unusual Gene Products for Pyran Ring Formation and Dioxan Biosynthesis. Chemistry & Biology 15(10):1046-1057.
Metsä-Ketelä, M., Niemi, J., Mäntsälä, P., and Schneider, G. (2008) Anthracycline Biosynthesis: Genes, Enzymes and Mechanisms (review) in Top Curr Chem, Springer Berlin / Heidelberg.
Niemi. J., Metsä-Ketelä, M., Schneider, G., and Mäntsälä, P. (2008) Biosynthetic Anthracycline Variants (review) in Top Curr Chem, Springer Berlin / Heidelberg.
Kallio, P., Liu, Z., Mäntsälä, P., Niemi, J. and Metsä-Ketelä, M. (2008) Sequential action of two flavoenzymes PgaE and PgaM in angucycline biosynthesis: chemoenzymatic synthesis of gaudimycin C. Chemistry & Biology 15(2):157-66.
Kallio, P., Liu, Z., Mäntsälä, P., Niemi, J., Metsä-Ketelä, M. (2008) A Nested Gene in Streptomyces Bacteria Encodes a Protein Involved in Quaternary Complex Formation. .J. Mol. Biol. 375(5): 1212-1221.
Koskiniemi, H., Metsä-Ketelä, M., Dobritzsch, D., Kallio, P., Korhonen, H., Mäntsälä, P., Schneider, G., Niemi, J.(2007) Crystal Structures of Two Aromatic Hydroxylases Involved in the Early Tailoring Steps of Angucycline Biosynthesis. J Mol Biol. 372(3):633-48.
Alexeev, I., Sultana, A., Mäntsälä, P., Niemi, J. and Schneider G. (2007) AknOx from the biosynthetic pathway of the antibiotic aclacinomycin is an unusual flavoenzyme with a dual active site. Proc Natl Acad Sci USA. 104(15):6170-5.
Sultana, A., Alexeev, I., Kursula, I., Mäntsälä, P., Niemi, J., and Schneider G. (2007) Structure determination by multiwavelength anomalous diffraction of aclacinomycin oxidoreductase: indications of multidomain pseudomerohedral twinning. Acta Cryst. D63, 149-159.
Crystal structures of SnoaL2 and AclR - two putative hydroxylases in the biosynthesis of aromatic polyketide antibiotics (2006) Beinker, P., Lohkamp, B., Peltonen, T., Niemi, J., Mäntsälä, P., Schneider, G. J. Mol. Biol. 359(3):728-40.
Kallio, P., Sultana, A., Niemi, J., Mäntsälä, P. and Schneider, G. (2006) Crystal structure of the polyketide cyclase AknH with bound substrate and product analogue: implications for catalytic mechanism and product stereoselectivity, J. Mol. Biol. 357(1):210-20.
Jansson A., Koskiniemi H., Erola A., Wang J., Mäntsälä P., Schneider G., Niemi J. (2005) Aclacinomycin-10-hydroxylase is a novel substrate-assisted hydroxylase requiring S-adenosyl-L-methionine as cofactor. J. Biol. Chem. 280(5): 3636-3644.
Jansson, A., Koskiniemi, Mäntsälä P., Niemi J., Schneider G.H., (2004) Crystal structure of a ternary complex of DnrK, a methyltransferase in daunorubicin biosynthesis, with bound products. J. Biol. Chem. Sep 24;279(39):41149-56.
Sultana, A., Kallio, P., Jansson, A., Wang, J-S., Niemi, J., Mäntsälä, P. and Schneider, G. (2004) Crystallization and preliminary crystallographic data of SnoaL, a polyketide cyclase in nogalamycin biosynthesis. Acta Crystallogr. D Biol. Crystallogr. 60(Pt 6):1118-2000.
Sultana, A., Kallio, P., Jansson, A., Wang, J-S., Niemi, J., Mäntsälä, P. and Schneider, G. (2004) Structure of the polyketide cyclase SnoaL reveals a novel mechanism for enzymatic aldol condensation EMBO J. 5;23(9):1911-21.
Jansson, A., Niemi, J., Mäntsälä, P. and Schneider, G. (2003) Crystallization and preliminary X-ray diffraction studies on aclacinomycin-10-methyl esterase and aclacinomycin-10-hydroxylase from Streptomyces purpurascens Acta Crystallogr. D Biol. Crystallogr. 59(Pt 9):1637-9.
Jansson, A., Niemi, J., Mäntsälä, P. and Schneider, G. (2003) Crystal structure of aclacinomycin methylesterase with bound product analoques: implications for anthracycline recognition and mechanism J. Biol. Chem. 278(40):39006-13.
Jansson A, Niemi J, Lindqvist Y, Mantsala P, Schneider G. (2003) Crystal structure of aclacinomycin-10-hydroxylase, a S-adenosyl-L-methionine-dependent methyltransferase homolog involved in anthracycline biosynthesis in Streptomyces purpurascens. J Mol Biol. Nov 21;334(2):269-80.
Niemi,J., Kantola,J., Ylihonko,K. & Mäntsälä, P. (2002) Anthracycline biosynthesis: stps, enzymes and genes (review) in Microbial secondary metabolites: biosynthesis, genetics and regulation (eds. Francisco Fierro & Juan Francisco Martin). Research Signpost 37/661, Kerala, India.
Wang,Y., Niemi, J. and Mäntsälä, P. (2002) Modification of aklavinone and aclacinomycins in vitro and in vivo by rhodomycin biosynthesis gene products. FEMS Microbiol. Lett. 208:117-122.
Wang,Y., Niemi,J., Airas,K., Ylihonko,K., Hakala,J. & Mäntsälä,P. (2000) Modifications of aclacinomycin T by aclacinomycin methyl esterase (RdmC) and aclacinomycin-10-hydroxylase (RdmB) from Streptomyces purpurascens. Biochim. Biophys Acta 1480:191-200.
Niemi,J., Wang, Y,. Airas,K., Ylihonko,K., Hakala,J. & Mäntsälä,P. (1999) Characterization of aklavinone 11-hydroxylase from Streptomyces purpurascens. Biochim. Biophys Acta 1430:57-64.
Kunnari,T., Niemi,J., Ylihonko,K., Mäntsälä,P., and Hakala,J. (1997) Hybrid anthracyclines by a genetically engineered Streptomyces galilaeus mutant. Bioorg. Med. Chem. Lett. 7:725-726.
Niemi,J., and Mäntsälä, P. (1995) Nucleotide sequence and expression of genes from Streptomyces purpurascens, that cause the production of new anthracyclines in S. galilaeus. J. Bacteriol. 177:2942-2945.
Niemi,J.,Ylihonko,K.,Hakala,J.,Kopio,A.,Pärssinen,A.,and Mäntsälä,P. (1994) Hybrid anthracycline antibiotics: production of new anthracyclines by cloned genes from Streptomyces purpurascens in Streptomyces galilaeus. Microbiol. 140:1351-1358
Ylihonko K, Hakala J, Niemi J, Lundell J, Mäntsälä P. (1994) Isolation and characterization of aclacinomycin A-non-producing Streptomyces galilaeus (ATCC 31615) mutants. Microbiology. 1994 Jun;140 ( Pt 6):1359-65.
>Current research in biochemistry