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FOR 1220:  Prosthetic groups: transport and insertion - PROTRAIN

Fachliche Zuordnung Biologie
Chemie
Förderung Förderung von 2009 bis 2016
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 100799727
 
Erstellungsjahr 2017

Zusammenfassung der Projektergebnisse

Enzymatic reactions are the driving force of metabolism. Complex cofactors and prosthetic groups of enzymes mediate the catalysis of challenging chemical reactions. While the biosynthesis of many prosthetic groups is well studied, their transport and regulated insertion into target enzymes is only poorly understood. Based on our long standing background in biosynthesis und functionality of prosthetic groups, we focus in Braunschweig with nine projects on the investigation of the unknown molecular strategies for transport and insertion of molybdenum cofactors (Moco) and hemes into enzymes. The main objective of the Research Group is to fill the gap in our knowledge about (1) what happens with the prosthetic groups heme and Moco subsequent to their biosynthesis, and (2) how is the process of insertion of these groups into their cognate apo-enzymes catalyzed. On the basis of the results from the first funding period, we sharpened and focussed our aims for the second period and incorporated three more groups (TP8, TP10, TP11) that provided additional key technologies for the PROTRAIN research unit, thus broadening our scope. In summary, we reached our goals: For objective 1, we identified and characterized both for eukaryotic Moco and bacterial heme novel proteins that are involved in transport of these prosthetic groups beyond biosynthesis. For objective 2, namely insertion, we also reached the goal in the way that these novel proteins were shown to be able to insert the prosthetic group into the respective apo-enzyme. However, the detailed mechanism for insertion has to be studied in the future. To name only a few: • A family of 8 Moco-binding proteins has been identified, characterized and localized in the plant Arabidopsis thaliana. They interact both with the Moco-donor protein Cnx1 and with the target protein nitrate reductase. • The atomic mechanism for the insertion of molybdenum into molybdopterin catalyzed by the Moco-donor protein Cnx1 was uncovered. Here we won the front cover page of the Biochemical Journal (2016) • For xanthine oxidase, the sequence of insertion of its three types of prosthetic groups has been determined, and a mechanism for the insertion of its Moco has been put forward. • The novel bacterial heme-binding protein HemW and its eukaryotic orthologue RSAD1 were identified as novel radical SAM proteins with heme chaperone function. • The maturation complex for NirS was identified, consisting of NirF, NirN and NirS, all three proteins are interacting with each other in vivo. All these results were only made possible through a tight collaboration between the single project groups: TP6 has synthesized fluorescent linkers, substrates, heme derivatives and Moco-derivatives, TP10 produced local chemical probes for the study of heme transfer processes and won the front cover page of the European Journal of Inorganic Chemistry, TP11 provided the proteomics platform, and our monoclonal antibody facility (TP8) has generated 149 monoclonal antibodies for all projects. Among others, publications appeared in Nature, PNAS and J Biol Chem. PROTRAIN also helped to shape the long-term profile of our Faculty of Life Sciences (biochemistry became one out of four strategic research focusses), led to the appointment of new biochemistry-oriented professors, led to establish the new Masterstudiengang "Biochemie / Chemische Biologie" at our university, was the corner stone to set up the novel "Braunschweig Center for Integrated Systems Biology BRICS" and finally formed the basis to successfully set up our new DFG-Graduiertenkolleg "Protein Complex Assembly" in 2016, where 7 out of 9 former PROTRAIN groups participate.

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