Luciana Hannibal, PhD
Research Group Leader
Head of the Metabolomics Core Facility
Project Leader and Scientific Board Member of EHOD
E: luciana.hannibal@uniklinik-freiburg.de
T: +49 (0)761 270 43710
Medical Center– University of Freiburg
Department of Pediatrics
Department of General Pediatrics, Adolescent Medicine and Neonatology
Elsässerstr. 2Q
79110 Freiburg
Germany
Our research investigates rare diseases of B-vitamin metabolism with a strong focus on genetic determinants of vitamin B12 deficiency (Figure 1). Vitamins of the B-group, namely pyridoxal phosphate (B6), folate (B9) and cobalamin (B12) are essential for the methionine cycle, one-carbon metabolism and transsulfuration reactions. We investigate how mutations in proteins and enzymes disrupt activity, cofactor binding, redox signaling, and protein-protein interactions (Figure 2), and their impact on disease onset, progression and phenotype heterogeneity. Using a combination of biophysical, omics, mass spectrometry, site-directed mutagenesis, and cell culture methodologies we seek to elucidate the molecular determinants of phenotype heterogeneity in genetic diseases of metabolism.
Figure 1: Cellular roadmap of cobalamin utilization and genetic determinants of inborn errors of metabolism (cblA-cblX, and mut). From Hannibal et al. 2016.
Figure 2: Structure of human MMACHC with bound cobalamin. Glutathione binding residues are shown in purple. From Hannibal, L and Jacobsen, DW, 2017.
Our methodological approach:
- Metabolic labeling in cell culture
- Targeted metabolic profiling by liquid chromatography and mass spectrometry
- Genetic engineering of proteins and in silico function prediction
- Recombinant protein expression and high-scale purification
- Rapid kinetics enzymology by stopped-flow
- Clinical Metabolomics
Our major research questions are:
1) Do protein and metabolite changes drive clinical manifestations in inborn errors of metabolism?
2) Do these pathology-specific features change during lifetime; i.e. as children become adolescents and adults?
3) Could we target these metabolic features (proteins, enzymes, metabolites) and correct the metabolic defect via repurposing of existing drugs or the development of new therapies?
TEAM
Our group approaches scientific questions using a variety of methodologies that require multidisciplinary expertise. Students and professionals in the fields of chemistry, pharmacy, biology and medicine are welcome to submit applications for undergraduate and graduate studies and research fellowships in translational research.
BASIC RESEARCH
Enzymology and repair of pathogenic variants of the human MMACHC protein of combined homocystinuria and methylmalonic aciduria
- Anna Esser (MD student)
- Srijan Mukherjee (Master Student)
- Katharina Klotz (Technical Assistant)
Bioactivity and testing of new cobalamin derivatives for the treatment of inborn errors of metabolism
- Srijan Mukherjee (Master Student)
Targeted metabolomics analysis of inborn errors of metabolism that lead to energy deficiency
- Nahuel R. Marziali (MD student)
- Alexandra Altmann (MD student)
- Julia Durif (MD student)
- Katharina Klotz (Technician in training)
Biosynthesis and detection of hydrogen sulfide in cystathionine beta synthase deficiency, classic homocystinuria
- Joanna Myszkowzka (MD student)
Natural and engineered variants of cytochrome c: conformational and functional analysis
- Florencia Tomasina (PhD student, collaboration with Prof. Dr. Rafael Radi)
CLINICAL RESEARCH
Clinical research projects are carried out in collaboration with PD. Dr. Sarah Grünert.
Elevated plasma vitamin B12 in inborn errors of metabolism
- Alexandra Altmann (MD student)
- Julia Durif (MD student)
- Julia Hinkel (MD student)
Metabolomic biomarkers of vascular health in patients with glycogen storage diseases
- Johannes Schmitt (MD student)
- Jule Theimer (MD student)
- Katharina Klotz (Technician in training)
ALUMNI
- Melissa Klenzendorf, RA (currently at CIBSS, University of Freiburg, Germany)
- Valerie Chaumet, MSc (currently pursuing PhD studies, Saarland University, Germany)
- Carla Ojeda, MSc (IMBS graduate, currently in Ecuador)
- Segun Tanimowo, Dr. med. (IMBS graduate, currently practicing medicine, UK)
- Victoria Wingert, MSc. (currently in industry, Germany)
- Sidney Behringer, MSc. (currently in industry, Switzerland)
- Suelen Basgalupp, PhD. (currently pursuing postdoctoral research, Brazil)
SELECTED RECENT PUBLICATIONS
For a complete publication list for Luciana Hannibal, please use the following links:
PubMed:https://www.ncbi.nlm.nih.gov/pubmed/?term=Luciana+Hannibal
ORCID: https://orcid.org/0000-0002-0911-5758
Scopus: https://www2.scopus.com/authid/detail.uri?authorId=16306673300
- Thiolatocobalamins repair the activity of pathogenic variants of the human cobalamin processing enzyme CblC. Wingert V, Mukherjee S, Esser AJ, Behringer S, Tanimowo S, Klenzendorf M, Derevenkov IA, Makarov SV, Jacobsen DW, Spiekerkoetter U, Hannibal L. Biochimie. 2020 Oct 22:S0300-9084(20)30264-9. doi: 10.1016/j.biochi.2020.10.006. PMID: 33190793
- Targeted metabolic profiling of methionine cycle metabolites and redox thiol pools in mammalian plasma, cells and urine. Behringer S, Wingert V, Oria V, Schumann A, Grünert SC, Cieslar-Pobuda A, Kölker S, Lederer AK, Jacobsen DW, Staerk J, Schilling O, Spiekerkoetter U, Hannibal L* Metabolites, 2019, 9, 235, 1-27. doi: 10.3390/metabo9100235.
- Glyceraldehyde-3-phosphate dehydrogenase is a chaperone that allocates labile heme in cells. Sweeny EA, Singh AB, Chakravarti R, Martinez-Guzman O, Saini A, Haque MM, Garee G, Dans PD, Hannibal L, Reddi AR, Stuehr DJ. J Biol Chem. 2018 Sep 14;293(37):14557-14568. doi: 10.1074/jbc.RA118.004169.
- Transcellular transport of cobalamin in aortic endothelial cells. Hannibal L*, Bolisetty K, Axhemi A, DiBello PM, Quadros EV, Fedosov S, Jacobsen DW. FASEB J. 2018 Oct;32(10):5506-5519. doi: 10.1096/fj.201701141RR.
- Dissecting structural and electronic effects in inducible nitric oxide synthase. Hannibal L*, Page RC, Haque MM, Bolisetty K, Yu Z, Misra S, Stuehr DJ*. Biochem J. 2015 Apr 1;467(1):153-65. doi: 10.1042/BJ20141319.
PATENTS AND INVENTION DISCLOSURES
International Patent Application Nr. PCT/EP2018/063597, Publication Nr. WO/2018/215578. Cobalamin derivatives and their use for the treatment of diseases caused by lack of vitamin B12 supply. Filing year: 2017
Invention Disclosure ZEE20170213. A capture method for the accurate and real-time detection of hydrogen sulfide (H2S) in biological samples. Filing year: 2017
COLLABORATIONS, CO-OPERATIONS AND NETWORKS
Networks and Cooperations
- Project leader and Scientific Board member of the European Network and Registry for Homocystinurias and Methylation Defects (EHOD)
- Instructor and Supervisor, International Master/PhD Program in Biomedical Sciences (IMBS Program)
- Council Member and Committee Chair of Society for Redox Biology and Medicine (SfRBM)
Collaboration Partners:
- Donald W. Jacobsen, Lerner Research Institute, Cleveland Clinic, USA.
- Dennis Stuehr, Lerner Research Institute, Cleveland Clinic, USA
- Ralf Brandes and Flavia de Rezende, Vascular Center, University of Frankfurt, Germany.
- Oliver Schilling, Department of Pathology, University Hospital Freiburg, Germany
- Roman Huber and Ann-Kathrin Lederer, Department of Complementary Medicine, University Hospital Freiburg, Germany
- Rafael Radi, CEINBIO, University of the Republic, Uruguay
- Judith Staerke, Nordic EMBL, Oslo, Norway
- Sergei Makarov and Ilia Dereven’kov, University of Ivanonovo, Russia
- Sean Froese and Matthias Baumgartner, Children’s Hospital Zürich, Zürich, Switzerland
- Christian Neusüß, Hochschule Aalen, Aalen, Germany
- Jerome Feige, Nestle Institute of Health Sciences, Lausanne, Switzerland
FUNDING
Nestle Institute of Health Sciences, Lausanne, Switzerland
FCE, National Agency for Investigation and Innovation, Montevideo, Uruguay
Medical Center – University of Freiburg, Germany
Intramural funding program “Support for Core Facilities”, Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany