Bernhard Kadenbach

Bernhard Kaden Bach ( born August 21, 1933, Luckenwalde ) is a German biochemist with focus on structure and function of the mitochondrial cytochrome c oxidase, who worked as a professor in the Department of Chemistry, Philipps- University of Marburg.

Life

Academic career

Kaden Bernhard Bach was born the fifth of eight children of the commercial school teacher Bernhard Kaden Bach and his wife Elfriede (born Brix) in Luckenwalde. After graduation in 1952 at the Gerhard -Hauptmann School in Luckenwalde Kadenbach studied chemistry in 1952 at the Humboldt University in Berlin - at that time Robert Havemann was Dean of the Faculty of Science and Director of the Institute of Physical Chemistry. Kaden Bach graduated in 1959 with a diploma. The thesis under the supervision of the organic chemist Otto Neunhoeffer took place in the Robert Rössle Cancer Clinic of the Academy of Sciences of the GDR ( DAdW ) in Berlin-Buch, then one of the most renowned biomedical research clinics in the Eastern Bloc countries.

From 1959 to 1961 Kaden Bach worked at the same place as a research assistant. During this time he completed in 1960, a year of research in the laboratory of Lars Ernster and Lindberg Olaf at Wenner -Gren Institute, Stockholm University. Kaden Bach returned in December 1960 after East Berlin. Since Otto Neunhoeffer had left Berlin in 1960 to go to the West at the University of the Saarland, Saarbrücken, Kaden Bach began his doctoral work under Samuel Mitja Rapoport. End of August 1961 finally left Kadenbach the GDR with false papers.

In 1961, a residency followed by Theodor books at the Institute of Physiological Chemistry, Philipps- University of Marburg, the Kadenbach 1964 with the graduation, followed by a DFG research fellowship followed at the same location until 1968. From 1969 to 1971 he was a research assistant at the Department of Physical Biochemistry at the Ludwig- Maximilians- Universität München Martin Klingenberg, who had also worked with Theodor books in Marburg mitochondria, and whose interest was the ADP -ATP transporter.

Kadenbach 1970 habilitation at the University of Konstanz and worked from 1971 to 1973 as senior assistant and lecturer in the Laboratory of Biochemistry, Swiss Federal Institute of Technology Zurich with Carl Martius.

In October 1973, Kaden Bach was appointed Professor of Biochemistry at the Department of Chemistry, Philipps- University of Marburg, which he held until his retirement in 1998.

From 2001 to 2011 Kaden Bach served as an active scientist in DFG-funded projects continue to two graduate students in the Biomedical Research Centre ( BMFZ ) at the Hospital of the Philipps- University of Marburg and ensured the supervision of technical staff in the laboratory of cardiac surgery.

Research

From 1973 to 2010 76 dissertations were made ​​chemistry / biochemistry in the compartment under the leadership of Kaden Bach, and 45 graduate students completed a doctorate (theses by research ): 31 thematically to cytochrome c oxidase, 7 to mitochondrial myopathies, 4 for mitochondrial phosphate transport and 3 to biochemical and biomedical methodology and analysis.

Mitochondrial phosphate transport

From 1973 to 1982, when neither the gene nor the amino acid sequence of the mitochondrial phosphate transport protein were known, Kaden Bach and co-workers studied phosphate binding of mitochondrial extracts and phosphate uptake in isolated mitochondria. In the latter case, the competitive inhibition of transport by reversible sulfhydryl reagents was studied (organic mercury compound such as mersalyl and salts of Ethylmercurithiosalicylsäure ) and the irreversible SH inhibitor N- ethylmaleimide, on the one hand, the specificity of the phosphate transporter compared with the dicarboxylate transporter, a other member of the family of mitochondrial carriers, delineate, and secondly to determine the substrate specificity of the transmembrane protein.

For the purification of the phosphate transporter fractions mitochondrial membranes were solubilized by non- ionic detergents and partly purified by hydroxyapatite and other stationary phases, to a protein analytical identification of the phosphate transporter by SDS-PAGE was possible (Mr 32 kDa). Reconstitution of the purified phosphate transporter in liposomes showed specific inhibitable phosphate transport, which showed a stimulated activity in the presence of mitochondria in naturally occurring cardiolipin.

Cytochrome c oxidase (COX)

Expression

Using the example of cytochrome c Kadenbach examined towards the end of the 1960s the cytoplasmic biosynthesis of mitochondrial proteins. He showed that some subunits of cytochrome c oxidase ( COX) in the cytosol, mitochondria, and other (ie, inside the mitochondria) are synthesized.

Subunits and cDNAs

1983 reported Kadenbach and employees by protein analytically that consist of various mammals mitochondria purified COX- protein complexes each consisting of 13 individual subunits. This large number of distinct subunits was long time not recognized under Mitochondriologen and hotly debated. Only 13 years later the final proof was made by the elucidation of the crystal structure of COX- multimer by Yoshikawa et al, whereby the position of the 13 proteins were visible to each other.

Although COX- complexes have the same enzymatic function in bacterial and mammalian, bacterial COX complexes contain only 3 subunits. For some of the 10 additional subunits in the mammalian regulatory functions were detected. Against each of the 13 subunits of COX polyclonal and monoclonal antibodies were produced in Marburg. For the first time tissue-specific isoforms of COX subunits VIa, VIIa, and VIII described, and shown differences in the kinetic activity of the isolated from different organs COX. The variable expression of isoenzymes of COX was detected by immunohistochemistry in different muscle fibers of man.

The genes ( cDNAs ) for the two (heart and liver ) isoforms of the subunit VIa as well as for other subunits were isolated and sequenced and the chromosomal gene structure for the subunit VIc and VIa were determined. In human tissue, the development-specific ( fetal / adult) expression of the isoforms could be demonstrated.

Kinetics and regulation

Binding studies of Kaden Bach and co-workers showed in isolated COX from beef heart 10 high-affinity ADP- binding sites. These 10 ADP binding sites in the crystal structure was confirmed by incorporation of 10 Cholatmolekülen ( similar space structure). Measurements of the stoichiometry of the proton transport of COX isolated reconstituted in liposomes confirmed functional regulation by the ADP / ATP ratio.

Another allosteric mechanism of respiratory control by the ATP / ADP ratio was found by binding specifically to the subunit IV. Work 2000-2011 led Kadenbach eventually to the formulation of a hypothesis concerning the role of COX- regulation in terms of the aging process and to the development of degenerative diseases in humans and animals.

Mitochondrial myopathies

The antibodies produced in Kaden 's group of against COX subunits were used for immunohistochemical detection of mitochondrial myopathy with COX defect. In collaboration with Josef Müller- hump was the first time to demonstrate the increase of COX- defective cells in the muscle and liver of healthy people as they age.

That of the " mispairing PCR" method, point mutations have been identified in samples of patients with MERRF syndrome and shown to be common cause of various neuromuscular diseases. In addition, using two different methods of detection found that the increase even in healthy subjects for MERRF characteristic point mutations with age.

It has been postulated that the life of the human being is also limited by the fact that COX- deficient cells resulting from random mutations of the mitochondrial DNA (mtDNA) that accumulate with increasing age.

Memberships

• Member of Society for Biochemistry and Molecular Biology since 1963
• Member of the New York Academy of Sciences since 1990

Publications

From 1959 to 2012 Kadenbach published 237 articles in national and international journals. The following publications are especially noteworthy:

• P. Merle and B. Kaden Bach: The subunit composition of mammalian cytochrome c oxidase, Eur J Biochem 105, 499-507 (1980).
• B. Kaden Bach, P. Mende, H.V.J. Kolbe, I. Stipani and F. Palmieri: The mitochondrial phosphate carrier HAS to essential requirement for cardiolipin, FEBS Lett. 139, 109-112 (1982).
• A. Schlerf, M. Droste, M. Winter and B. Kaden Bach: Characterization of two different genes (cDNA ) for cytochrome c oxidase subunit VIa from heart and liver of the rat, EMBO J. 7, 2387-2391 (1988).
• G. Bonne, P. Seibel, S. Possekel, C. Marsac and B. Kaden Bach: cytochrome c oxidase Expression of humen subunits falling on fetal development, Eur J. Biochem. 217, 1099-1107 (1993).
• Frank V. and B. Kaden Bach: regulation of the H / e - stoichiometry of cytochrome c oxidase from bovine heart by intraliposomal ATP / ADP ratios, FEBS Lett. 382, 121-124 (1996).
• J. Napiwotzki, K. Shinzawa - Itoh, S. Yoshikawa and B. Kaden Bach: ATP and ADP bind to cytochrome c oxidase and regulate its activity, Biol Chem 378, 1013-1021 (1997).
• S. Arnold and B. Kaden Bach: Priority Paper: Cell respiration is controlled by ATP, allosteric inhibitor of cytochrome c to oxidase, Eur J. Biochem. 249, 350-354 (1997).
• B. Kaden Bach and S. Arnold: Mini Review: A second mechanism of respiratory control, FEBS Lett. 447, 131-134 (1999).
• B. Ludwig, E. Bender, S. Arnold, M. hut man, I. Lee and B. Kaden Bach Cytochrome c oxidase and the regulation of oxidative phosphorylation, ChemBioChem. 2, 392-403 (2001).
• B. Kaden Bach, R. Ramzan, L. Wen, and S. Vogt: New extension of the Mitchell Theory for oxidative phosphorylation in mitochondria of living organisms, Biochim. Biophys. Acta. 1800, 205-212 (2010).
• B. Kaden Bach ( ed.): Mitochondrial Oxidative Phosphorylation. Nuclear - Encodes Genes, enzymes, regulation, and Pathophysiology ( Medical Advances in Medicine and Biology 748 ), Springer- Verlag ( 2012) ISBN 9,781,461,435,723th