TY  - JOUR
AB  - In the early 1930s, the chemical uncoupling agent 2,4-dinitrophenol (DNP) was promoted for the very first time as a powerful and effective weight loss pill but quickly withdrawn from the market due to its lack of tissue-selectivity with resulting dangerous side effects, including hyperthermia and death. Today, novel mitochondria- or tissue-targeted chemical uncouplers with higher safety and therapeutic values are under investigation in order to tackle obesity, diabetes and fatty liver disease. Moreover, in the past 20 years, transgenic mouse models were generated to understand the molecular and metabolic consequences of targeted uncoupling, expressing functional uncoupling protein 1 (UCP1) ectopically in white adipose tissue or skeletal muscle. Similar to the action of chemical mitochondrial uncouplers, UCP1 protein dissipates the proton gradient across the inner mitochondrial membrane, thus allowing maximum activity of the respiratory chain and compensatory increase in oxygen consumption, uncoupled from ATP synthesis. Consequently, targeted mitochondrial uncoupling in adipose tissue and skeletal muscle of UCP1-transgenic mice increased substrate metabolism and ameliorates obesity, hypertriglyceridemia and insulin resistance. Further, muscle-specific decrease in mitochondrial efficiency promotes a cell-autonomous and cell-non-autonomous adaptive metabolic remodeling with increased oxidative stress tolerance. This review provides an overview of novel chemical uncouplers as well as the metabolic consequences and adaptive processes of targeted mitochondrial uncoupling on metabolic health and survival.
AU  - Ost, M.*
AU  - Keipert, S.
AU  - Klaus, S.*
C1  - 50289
C2  - 42259
SP  - 77-85
TI  - Targeted mitochondrial uncoupling beyond UCP1 - The fine line between death and metabolic health.
JO  - Biochimie
VL  - 134
PY  - 2017
SN  - 0300-9084
ER  - 

TY  - JOUR
AB  - 17ß-Hydroxysteroid dehydrogenase from the fungus Cochliobolus lunatus (17ß-HSDcl) is an NADPH-dependent member of the short-chain dehydrogenase/ reductase superfamily. To study the catalytic properties of this enzyme, we prepared several specific mutations of 17ß-HSDcl (Tyr167Phe, His164Trp/Gly, Tyr212Ala). Wild-type 17ß-HSDcl and the 17ß-HSDcl mutants were evaluated by chromatographic, kinetic and thermodynamic means. The Tyr167Phe mutation resulted in a complete loss of enzyme activity, while substitution of His164 with Trp and Gly both resulted in higher specificity number (V/K) for the steroid substrates, which are mainly a consequence of easier accessibility of steroid substrates to the active-site hollow under optimized conditions. The Tyr212Ala mutant showed increased activity in the oxidative direction, which appears to be a consequence of increased NADPH dissociation. The kinetic characterizations and thermodynamic analyses also suggest that His164 and Tyr212 in 17ß-HSDcl have a role in the opening and closing of the active site of this enzyme and in the discrimination between oxidized and reduced coenzyme.
AU  - Kristan, K.*
AU  - Adamski, J.
AU  - Lanisnik Rizner, T.*
AU  - Stojan, J.*
C1  - 5866
C2  - 24476
SP  - 63-71
TI  - His164 regulates accessibility to the active site in fungal 17β-hydroxysteroid dehydrogenase.
JO  - Biochimie
VL  - 89
IS  - 1
PB  - Elsevier
PY  - 2007
SN  - 0300-9084
ER  - 

TY  - JOUR
AB  - N2 fixation, C2H2 reduction and H2 production in Rhodopseudomonas acidophila DSM 137 were shown to be stoichiometrically related in ratios of 1:2.8:2.8. The highest possible H2 oxidation rate has been calculated to be about 6 fold higher in Rhodopseudomonas acidophila DSM 137 than the maximum rate of H2 production. Nif- mutants were isolated and tested ; all of them had lost their ability to reduce C2H2 and to produce H2. In two nif- mutants hydrogenase activity and the capacity for autotrophic growth with H2 were also strongly diminished. Nif+ revertants not only regained their ability for C2H2 reduction and H2 production but also their full capacity for autotrophic growth with H2.
AU  - Siefert, E.
AU  - Pfennig, N.
C1  - 42437
C2  - 35831
SP  - 261-265
TI  - Hydrogen metabolism and nitrogen fixation in wild type and Nif- mutants of Rhodopseudomonas acidophila.
JO  - Biochimie
VL  - 60
IS  - 3
PY  - 1978
SN  - 0300-9084
ER  -