Arne Holmgren Group
Thioredoxin and glutaredoxin systems, new antibiotic principle, DNA synthesis, anticancer mechanisms, glutathione, redox signaling.
Proteins catalysing thiol-disulfide exchange reactions are required for many functions including electron transport to essential enzymes like ribonucleotide reductase for DNA synthesis, removal of hydrogen peroxide by peroxiredoxins to control oxidative stress and signaling by hydrogen peroxide or for general regulation of protein function by thiol redox control. Thioredoxin (Trx) and glutaredoxin (Grx) operate in thiol-disulfide reactions via two vicinal (CXYC) active site cysteine residues, which either form a disulfide (oxidized form) or a dithiol (reduced form). Trx is reduced to the dithiol form by NADPH and thioredoxin reductase (together called the thioredoxin system). Grx in contrast is reduced by the ubiquitous tripeptide glutathione (GSH) and GSSG in turn is reduced by NADPH and glutathione reductase (together called the glutaredoxin system). A large and growing number of functions in biological systems are known for Trx and Grx and the intimate interplay where glutathione and glutaredoxins act as a backup of thioredoxin reductase. Bacteria have a low molecular weight thioredoxin reductase which can be specifically targeted by the selenazol drug ebselen as a new antibiotic principle. In contrast mammalian cells have high molecular weight thioredoxin reductases with a penultimate essential selenocysteine residue and use ebselen as a substrate. Many anticancer electrophile drugs target the selenocysteine reside and convert the enzyme into a prooxidant producing reactive oxygen species leading to cell death.
Aims, results and future directions
Our aims are to understand the detailed mechanisms and role of thioredoxin and glutathione-glutaredoxin systems in redox reactions and control of physiological processes. We study the mechanism of ribonuceotide reductase, specifically how a swinging arm mechanism is used to reach into the active site and the replicative stress generated via effects from the redoxin systems causing rate-limiting synthesis of deoxyribonucleotides for DNA replication and repair. A new antibiotic principle is based on selective inhibition of the thioredoxin system in gram-positive bacteria and attempts to develop this into targeting also multiresistant gram-negative bacteria. Novel applications of drugs to target thioredoxin reductase in cancer cells causing oxidative stress and selective elimination of tumors is tested.
|Arne Holmgren||Professor, senior|