Venkatesan Research Group

Structural Biochemistry: Molecular machines of lipid metabolism and lipid transport
Cartoon representation and electron density of a protein

Research group information

Unit and faculty

Protein and Structural Biology
Faculty of Biochemistry and Molecular Medicine

Contact information

Research group leader

Contact person

Researchers

Research group description

Venkatesan research group’s core interests are to understand the processes of lipid metabolism and lipid transport at a molecular level with a focus on multi-functional enzymes and multi-protein complexes using a variety of biophysical, biochemical and structural biological approaches.

Lipids are essential constituents of cells and an important source of energy and carbon in living organisms ranging from bacteria to human. A multitude of proteins and enzymes exist in the cell to facilitate the synthesis, transport and degradation of lipids. Our group aims to understand the structure and function of enzyme and protein complexes involved in the transport and metabolism of lipids. Particular interest is on understanding the role of lipids in the survival of the pathogen Mycobacterium tuberculosis (Mtb). There are two major lines of research.

i) Enzymes of the β-oxidation pathway from human, E. coli and mycobacteria

Fatty acids are degraded in iterative cycles of four steps. A number of enzymes are involved in the β-oxidation pathway with varying substrate specificities. Our aim is to understand the structural and functional properties of these enzymes, in particular, on the assembly, substrate specificity and substrate channeling properties of the trifunctional β-oxidation enzyme (TFE) complex. Our group has determined the structures of TFEs and their sub-units from Mtb and E. coli.

ii) Mycobacterial mammalian-cell-entry (Mce) proteins

Mtb is one of the very few organisms which survives on the host lipids as a source of energy and carbon during the latent stage of infection. ABC transporters composed of the proteins encoded from the Mce1-4 operons are proposed to be involved in the transport of such lipids including cholesterol and fatty acids. Our group is working on these Mce-complexes to understand the assembly and lipid transport mechanism of these transporters.

Research group members

Rajaram Venkatesan (PhD, Docent, Group leader)

Rik Wierenga (PhD, Emeritus Professor, Project leader)

Group members: Row1: Rajaram Venkatesan, Perumal Perumal, Nora Tir, Ulaganathan Sivagnanam. Row2: Mohammad Asadur Rahman, Ramita Sulu, Mikko Hynönen, Amal Sarhan. Row3: Rik Wierenga, Subhadra Dalwani, Mubinur Rahman, Sudarshan Narasimha Murthy

Join us

We do not have any open PhD or postdoctoral positions at the moment. Contact Dr. Rajaram Venkatesan (rajaram.venkatesan@oulu.fi), if you are interested to know more about our projects and wish to apply for fellowships to join our group. Also, we are always open to take enthusiastic and motivated trainees and MSc pro-gradu students.

Publications

Selected publications

  1. Sah-Teli SK, Pinkas M, Hynönen MJ, Butcher SJ, Wierenga RK, Novacek J, Venkatesan R. Structural basis for different membrane-binding properties of E. coli anaerobic and human mitochondrial β-oxidation trifunctional enzymes. Structure. 2023 May 11:S0969-2126(23)00134-X. doi: 10.1016/j.str.2023.04.011. PMID: 37192613.
  2. Harijan RK, Dalwani S, Kiema TR, Venkatesan R Wierenga RK. Thiolase: a versatile biocatalyst employing CoA-thioester chemistry for making and breaking C-C bonds. Annual Review of Biochemistry 2023 92:1 doi: 10.1146/annurev-biochem-052521-033746. PMID: 37068769
  3. Murthy AV, Sulu R, Lebedev A, Salo AM, Korhonen K, Venkatesan R, Tu H, Bergmann U, Jänis J, Laitaoja M, Ruddock LW, Myllyharju J, Koski MK, Wierenga RK. Crystal structure of the collagen prolyl 4-hydroxylase (C-P4H) catalytic domain complexed with PDI: Toward a model of the C-P4H α2β2 tetramer. J Biol Chem. 2022 Dec;298(12):102614. doi: 10.1016/j.jbc.2022.102614. Epub 2022 Oct 18. PMID: 36265586; PMCID: PMC9676403.
  4. Dalwani S, Lampela O, Leprovost P, Schmitz W, Juffer AH, Wierenga RK, Venkatesan R. Substrate specificity and conformational flexibility properties of the Mycobacterium tuberculosis β-oxidation trifunctional enzyme. J Struct Biol. 2021 Sep;213(3):107776. doi: 10.1016/j.jsb.2021.107776. Epub 2021 Aug 8. PMID: 34371166.
  5. Alam J, Rahman FT, Sah-Teli SK, Venkatesan R, Koski MK, Autio KJ, Hiltunen JK, Kastaniotis AJ. Expression and analysis of the SAM-dependent RNA methyltransferase Rsm22 from Saccharomyces cerevisiae. Acta Crystallogr D Struct Biol. 2021 Jun 1;77(Pt 6):840-853. doi: 10.1107/S2059798321004149. Epub 2021 May 19. PMID: 34076597; PMCID: PMC8171064.
  6. Asthana P, Singh D, Pedersen JS, Hynönen MJ, Sulu R, Murthy AV, Laitaoja M, Jänis J, Riley LW, Venkatesan R. Structural insights into the substrate-binding proteins Mce1A and Mce4A from Mycobacterium tuberculosis. IUCrJ. 2021 Jul 28;8(Pt 5):757-774. doi: 10.1107/S2052252521006199. PMID: 34584737; PMCID: PMC8420772.
  7. Daniel E, Maksimainen MM, Smith N, Ratas V, Biterova E, Murthy SN, Rahman MT, Kiema TR, Sridhar S, Cordara G, Dalwani S, Venkatesan R, Prilusky J, Dym O, Lehtiö L, Koski MK, Ashton AW, SussmanJL, Wierenga, RK. IceBear: An intuitive and versatile web application for research data tracking from crystallization experiment to PDB deposition. Acta Cryst.D77, 151-163. doi: 10.1107/S2059798320015223
  8. Sridhar S, Schmitz W, Hiltunen JK, Venkatesan R, Bergmann U, Kiema TR, Wierenga RK. Crystallographic binding studies of rat peroxisomal multifunctional enzyme type 1 with 3-ketodecanoyl-CoA: capturing active and inactive states of its hydratase and dehydrogenase catalytic sites. Acta Cryst. D76, 2020; doi:0.1107/S2059798320013819
  9. Sah-Teli SK, Hynönen MJ, Sulu R, Dalwani S, Schmitz W, Wierenga RK, Venkatesan R Insights into the stability and substrate specificity of the E. coli aerobic β-oxidation trifunctional enzyme complex. J Struct Biol. 2020; 210(3):107494 doi: 10.1016/j.jsb.2020.107494
  10. Sah-Teli SK, Hynönen MJ, Schmitz W, Geraets JA, Seitsonen J, Pedersen JS, Butcher SJ, Wierenga RK, Venkatesan R. Complementary substrate specificity and distinct quaternary assembly of the Escherichia coli aerobic and anaerobic beta-oxidation trifunctional enzyme complexes. Biochem J. 2019; 476: 1975-1994 doi: 10.1042/BCJ20190314
  11. Venkatesan R, Sah-Teli SK, Awoniyi LO, Jiang G, Prus P, Kastaniotis AJ, Hiltunen JK, Wierenga RK, Chen Z#. Insights into mitochondrial fatty acid synthesis from the structure of heterotetrameric 3-ketoacyl-ACP reductase/3R-hydroxyacyl-CoA dehydrogenase. Nature Commun. 2014;5:4805. doi: 10.1038/ncomms5805
  12. Fukao T, Akiba K, Goto M, Kuwayama N, Morita M, Hori T, Aoyama Y, Venkatesan R, Wierenga R, Moriyama Y, Hashimoto T, Usuda N, Murayama K, Ohtake A, Hasegawa Y, Shigematsu Y, Hasegawa Y. The first case in Asia of 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (HSD10 disease) with atypical presentation. J Hum Genet. 2014; doi: 10.1038/jhg.2014.79
  13. Venkatesan R, Wierenga RK. Structure of mycobacterial β-oxidation trifunctional enzyme reveals its altered assembly and putative substrate channeling pathway. ACS Chemical Biology. 2013; 8:1063-1073
  14. Bisht S, Rajaram V, Bharath SR, Kalyani JN, Khan F, Rao AN, Savithri HS, Murthy MR. Crystal Structure of Escherichia coli diaminopropionate ammonia-lyase reveals mechanism of enzyme activation and catalysis. J Biol Chem. 2012; 287(24):20369-81
  15. Sharma S, Bhaumik P, Schmitz W, Venkatesan R, Hiltunen JK, Conzelmann E,Juffer AH, Wierenga RK. The enolization chemistry of a thioester-dependent racemase: the 1.4 Å crystal structure of a reaction intermediate complex characterized by detailed QM/MM calculations. J Phys Chem B. 2012; 116(11):3619-29

Alumni

  • Dr. Dhirendra Singh (Postdoctoral researcher, 2016-2021)
  • Dr. Pooja (Doctoral student, 2017-2021)
  • Dr. Shruthi Sridhar (Doctoral student, 2016-2021)
  • Dr. Shiv Kumar Sah-Teli (Doctoral student, 2014-2020)
  • Dr. Sandhanakrishnan Cattavarayane (Postdoctoral researcher, 2016)
  • Hao-Wei Lee (MSc student, 2010-2011)