Johan Thevelein
Nutrient Sensing and Signaling in Yeast
Biotechnological applications of yeast
VIB Department of Molecular Microbiology, K.U.Leuven

PhD: Univ. of Leuven, Leuven, Belgium, '81 Postdoc: Yale University, Connecticut, USA, '82-'83 Scientific Director, Dept. of Molecular Microbiology since 2002

e-mail phone +32 16 32 15 00 ADDRESS

Current team members
Group leader: Johan Thevelein
Staff scientists: Beatriz Bonini Monge, Elke Nevoigt, Françoise Dumortier, Peter Verhaert
Postdoctoral scientists: Dries Castermans, Griet Van Zeebroeck, Johan Kriel, Maria Remedios Foulquié y Moreno, Marta Rubio-Texeira, Yulia Popova
Ph.D. Students: Ben Souffriau, Georg Hubmann, Harish Kankipati, Jurgen Vandamme, Ken Peeters, Marlies Kimpe, Sarah Marinelli, Steven Haesendonckx, Stijn De Graeve, Tessa Moses, Thiago Martins Pais, Tom Den Abt, Wim Schepers, Yudi Yang
Visiting young scientist: Yoshiyuki Osabe
Support personnel: Catherina Coun, Eef Allegaert, Evy Vanderheyden, Kjell Lenaers, Mekonnen Demeke, Paul Vandecruys, Renata Wicik, Stephen Castermans, Thomas Talpe, Tom Adriany

Keywords
transceptors stress tolerance - flavour ester synthesis - bioethanol production - medical applications

Science

Research in our group is focussed on two major topics: 1. the molecular genetics and biochemistry of nutrient-sensing and -signaling in yeast (Saccharomyces cerevisiae). and 2. the use of industrial yeast strains for several biotechnological and medical applications

This has resulted in the discovery of several nutrient 'transceptors': proteins that combine the functions of transporter and receptor.
Nutrients do not only serve as substrates for production of energy and building blocks by cells, but they also exert dramatic regulatory effects on cells. Although some specific nutrient effects have been elucidated in great detail, how different nutrients affect major cellular activities like regulation of storage compound metabolism, stress tolerance and growth of the cells is not understood. Yeast provides a powerful model system to study such mechanisms.

The main emphasis in our yeast research on nutrient sensing and signaling is on the control of the Ras - cAMP - protein kinase A pathway. This is a major signaling pathway in eukaryotic cells. In yeast it controls major cellular activities like fermentation rate, storage compound metabolism, stress tolerance, growth of the cells and several developmental pathways. The pathway is strongly affected by all major nutrients: sugars, amino acids, ammonium, phosphate and sulfate. Glucose addition activates cAMP synthesis. Two sensing systems are involved in this
process: a G-protein coupled receptor (GPCR) system that acts in concert with a glucose-phosphorylation dependent system. The GPCR Gpr1 is a high-affinity sucrose and low-affinity glucose receptor. Residues located adjacent to the ligand-binding site have been identified using SCAM analysis. The Galpha protein Gpa2 of this GPCR system does not interact with classical beta/gamma subunits and activates a bypass pathway of adenylate cyclase directly affecting PKA. It is composed of the kelch repeat proteins Krh1 and Krh2. Gpr1 has several characteristics of a primitive GPCR. Recent work has revealed that its closest homologue in the yeast genome is Rgt2, a low-affinity glucose sensor with the same structure as a glucose transporter but without transport capacity. This has provided the first evidence that GPCR's may originate from nutrient transporters in evolution.

Addition of the other nutrients also activates the protein kinase A pathway but not through classical receptors or stimulation of cAMP synthesis. Elucidation of the amino acid, ammonium and phosphate sensing systems has led to the discovery of several nutrient 'transceptors': proteins that are, or are closely related to, transporters and also function as receptor. Amino acids are sensed by the Gap1 transceptor, which has become the best established and characterized example of a transporting transceptor. Ammonium and phosphate are mainly sensed by the transporting transceptors Mep2 and Pho84, respectively. SCAM analysis with
Gap1 and Pho84 has shown that the same nutrient-binding site is involved in transport and signaling. The discovery of nontransported agonists of the signaling function and non-signaling competitive inhibitors of the transport function of these transceptors has indicated that the substrate ligands must trigger for signaling a specific conformational change that may be part of but does not require the complete transport cycle. The precise mechanisms involved in amino acid, ammonium and phosphate sensing and signaling for activation of the protein kinase A pathway are a major focus of current research.

A second major focus in our group is the development of novel commercial yeast strains for several industrial
applications: production of bioethanol and alternative biofuel with 1st and 2nd generation substrates, beer brewing, wine and breezer production, baking, and production of specialty compounds. A novel genetic mapping technology has been developed which greatly facilitates the identification of genes involved in polygenic and quantitative properties, such as ethanol accumulation capacity, tolerance to different types of stress and flavour compound production. This will facilitate the development of improved industrial yeast strains. In addition, yeast is also used as a tool for the isolation and study of mammalian genes with medical interest, such as genes involved in Parkinson's disease, diabetes and glucose sensing in mammalian cells.

Press Release
See also press release (05/12/2008): Food can affect a cell in the same way hormones do based on a publication in Nature chemical biology (Van Zeebroeck et al., Nature chemical biology, 2008).

See also press release (01/08/2007): Plants and stress; key players on the thin line between life and death revealed based on a publication in Nature (Baena-González et al., Nature, 2007)

Van Zeebroeck G, Bonini B, Versele M, Thevelein J
Transport and signaling via the amino acid binding site of the yeast Gap1 amino acid transceptor
NAT CHEM BIOL 5, 45-52, 2009



Thevelein J, Voordeckers K
Functioning and evolutionary significance of nutrient transceptors
MOL BIOL EVOL 26, 2407-14, 2009



Peeters T, Louwet W, Gelade R, Nauwelaers D, Thevelein J, Versele M
Kelch-repeat proteins interacting with the Galpha protein Gpa2 bypass adenylate cyclase for direct regulation of protein kinase A in yeast
P NATL ACAD SCI USA 103, 13034-9, 2006



Van Nuland A, Vandormael P, Donaton M, Alenquer M, Lourenco A, Quintino E, Versele M, Thevelein J
Ammonium permease-based sensing mechanism for rapid ammonium activation of the protein kinase A pathway in yeast
MOL MICROBIOL 59, 1485-505, 2006



Kraakman L, Lemaire K, Ma P, Teunissen A, Donaton M, Van Dijck P, Winderickx J, De Winde J, Thevelein J
A Saccharomyces cerevisiae G-protein coupled receptor, Gpr1, is specifically required for glucose activation of the cAMP pathway during the transition to growth on glucose
MOL MICROBIOL 32, 1002-1012, 1999

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