Blocking the active site of thiolase

A key feature of the active site of the trypanosomal thiolase is the HDCF-loop (HIS-ASP-CYS-PHE), visualised in light blue.

A key feature of the active site of the trypanosomal thiolase is the HDCF-loop (HIS-ASP-CYS-PHE), visualised in light blue. © University of Oulu

Scientists at the University of Oulu, Finland, and at the HZB break new ground for drug discovery research in the fight against sleeping sickness

Scientists at the University of Oulu, Finland, and at the Helmholtz Center Berlin (HZB) have shown the way to new directions in drug development against African sleeping sickness and other tropical parasitic infections. This was based on the structural analysis of the enzyme thiolase, which plays a central role in lipid metabolism in the parasite that causes sleeping sickness. The researchers examined the biomolecule’s structure at the MX beamline of electron storage ring, BESSY II, at the HZB. (Biochemical J. 2013, DOI: 10.1042/BJ20130669)

Sleeping sicknesses – african trypanosomiasis, kala-azar, indian leishmaniasis – are infections caused by tropical parasites. Millions get sick from them each year and thousands end up dying. Anti-parasitic drugs are expensive and often have a host of unwanted side effects. In decades, there have been no new effective therapies. Reason enough for the World Health Organization (WHO) to consider research, which can lead to the development of new anti-parasitic drugs, a top priority.

Now, Prof. Rik Wierenga and his team at Oulu University have paved the way for this type of research by shedding light on the structure of the enzyme thiolase. Thiolase figures prominently in parasitic lipid metabolism. According to Wierenga, “key is knowing the geometry of the enzyme’s active site. This is the place where lipids that play a central role in parasitic metabolism attach and where chemical reactions that convert lipids into other substances take place.” Which is why it’s important to investigate the active site’s structure and function: “It enables us to develop lipid-like substances that firmly attach to the active site and block it.” The molecules that are involved represent the ideal starting points for new drug development.
Studies at BESSY of the enzyme thiolase have yielded a highly detailed image of thiolase’s active site. “We now have a much clearer idea of thiolase’s role in all this,” says Wierenga. “It would appear that the enzyme catalyzes the first step in the sterol biosynthesis pathway, which is important in a number of parasites.”

“The measurements of crystalline thiolase proteins we obtained at our MX beamline has helped to unravel the active site’s geometry,” says HZB’s own Dr. Manfred Weiss. One particular region of the protein called the HDCF loop turns out to be key. The structure, which lies deep within thiolase’s interior, was previously unknown. “Understanding the HDCF loop is the ideal starting point for the development of new anti-parasitic drugs,” adds Wierenga.

Original publication:
Harijan, R.K., Kiema, T.R., Karjalainen, M.P., Janardan, N., Murthy, M.R., Weiss. M.S., Michels, P.A., Wierenga, R.K. (2013) Crystal structures of SCP2-thiolases of Trypanosomatidae, human pathogens causing widespread tropical diseases: the importance for catalysis of the cysteine of the unique HDCF loop. Biochem J., 455, 119-130.

HS

  • Copy link

You might also be interested in

  • Porous Radical Organic framework improves lithium-sulphur batteries
    Science Highlight
    15.09.2025
    Porous Radical Organic framework improves lithium-sulphur batteries
    A team led by Prof. Yan Lu, HZB, and Prof. Arne Thomas, Technical University of Berlin, has developed a material that enhances the capacity and stability of lithium-sulphur batteries. The material is based on polymers that form a framework with open pores (known as radical-cationic covalent organic frameworks or COFs). Catalytically accelerated reactions take place in these pores, firmly trapping polysulphides, which would shorten the battery life. Some of the experimental analyses were conducted at the BAMline at BESSY II.
  • Metallic nanocatalysts: what really happens during catalysis
    Science Highlight
    10.09.2025
    Metallic nanocatalysts: what really happens during catalysis
    Using a combination of spectromicroscopy at BESSY II and microscopic analyses at DESY's NanoLab, a team has gained new insights into the chemical behaviour of nanocatalysts during catalysis. The nanoparticles consisted of a platinum core with a rhodium shell. This configuration allows a better understanding of structural changes in, for example, rhodium-platinum catalysts for emission control. The results show that under typical catalytic conditions, some of the rhodium in the shell can diffuse into the interior of the nanoparticles. However, most of it remains on the surface and oxidises. This process is strongly dependent on the surface orientation of the nanoparticle facets.
  • Key technology for a future without fossil fuels
    Interview
    21.08.2025
    Key technology for a future without fossil fuels
    In June and July 2025, catalyst researcher Nico Fischer spent some time at HZB. It was his sabbatical, he was relieved of his duties as Director of the Catalysis Institute in Cape Town for several months and was able to focus on research only. His institute is collaborating with HZB on two projects that aim to develop environmentally friendly alternatives using innovative catalyst technologies. The questions were asked by Antonia Rötger, HZB.