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)
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)
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)
VITAMIN B12 | HOMOCYSTINURIA | METHYLMALONIC ACIDURIA
- Anna Esser (MD student)
- Joanna Myszkowzka (MD student)
- Sara Schröter (MD student)
- Alexandra Altmann (MD student)
- Julia Durif (MD student)
- Martin Suarez-Alvarez (BSc student)
METABOLOMICS | INBORN ERRORS OF METABOLISM
- Dr. Lennart Moritz (Clinician Scientist)
- Victoria Wingert (Lead Scientist)
- Anna Fosu (MSc Student)
- Sandra Ehret (Technical Assistant)
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)
Clinical research projects are carried out in collaboration with other scientists:
Prof. Dr. Roman Huber, Dr. Ann-Kathrin Lederer and Dr. Maximilian Storz: Nutrition and Vitamin B12 status in plant-based diets
Prof. Martina Huemer: Vitamin B12 status in mother-baby dyads during pregnancy and first year of life
Prof. Dr. Ute Spiekerkötter: Fatty acid oxidation disorders, energy deficiency in renal disease
Dr. Dr. Anke Schumann: Inborn errors of metabolism with renal disease
ALUMNI
- Segun Tanimowo, MD. (IMBS graduate, currently practicing medicine, UK)
- Suelen Basgalupp, PhD. (currently pursuing postdoctoral research, Brazil)
- Nahuel R. Marziali, MD. (currently pursuing medical residence, University of Lyon, France)
- Melissa Klenzendorf, TA (currently at BioNTech, Mainz, Germany)
- Katharina Klotz, TA (currently in industry, Switzerland)
- Valerie Chaumet, MSc (currently pursuing PhD studies, Saarland,Germany)
- Carla Ojeda, MSc (IMBS graduate, currently in Ecuador)
- Victoria Wingert, MSc. (rejoined our team on November 2023)
- Sidney Behringer, MSc. (currently in industry, Switzerland)
- Srijan Muhkerjee, MSc. (IMBS graduate, currently pursuing PhD studies, Charles University, Prague, Czeck Republic)
- Aida Corrillero Bravo (Erasmus program, University of Extremadura, Spain)
- Maria Nieves Ligero Aguilera (Erasmus program, University of Extremadura, Spain)
- Laura Uricher, FSJ fellow (University Hospital Freiburg, Germany)
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
- The importance of vitamin B12 for individuals choosing plant-based diets. Niklewicz A, Smith AD, Smith A, Holzer A, Klein A, McCaddon A, Molloy AM, Wolffenbuttel BHR, Nexo E, McNulty H, Refsum H, Gueant JL, Dib MJ, Ward M, Murphy M, Green R, Ahmadi KR, Hannibal L, Warren MJ, Owen PJ; CluB-12.Eur J Nutr. 2023 Apr;62(3):1551-1559. doi: 10.1007/s00394-022-03025-4.
- Metabolic phenotyping in phenylketonuria reveals disease clustering independently of metabolic control. Moritz L, Klotz K, Grünert SC, Hannibal L, Spiekerkoetter U. Mol Genet Metab. 2023 Mar;138(3):107509. doi: 10.1016/j.ymgme.2023.107509.
- Versatile enzymology and heterogeneous phenotypes in cobalamin complementation type C disease. Esser AJ, Mukherjee S, Dereven’kov IA, Makarov SV, Jacobsen DW, Spiekerkoetter U, Hannibal L. 2022 Aug 18;25(9):104981. doi: 10.1016/j.isci.2022.104981.
- 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.
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)
- Committee Member of cluB-12: Understanding Vitamin B12
- Scientific and Executive Board member of the European Network and Registry for Homocystinurias and Methylation Defects (EHOD)
- Co-Lead of DGMet Working Group Metabolomic Platforms
- Lecturer and Scientific Supervisor, International Master/PhD Program in Biomedical Sciences (IMBS Program)
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, Ann-Kathrin Lederer and Maximilian Storz Department of Complementary Medicine, 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
- Melanie Föll, Institute of Pathology, University Hospital Freiburg, Germany
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