You are here
Rutgers-New Jersey Medical School; Poznań University of Life Sciences
Areas of Interest:
Alzheimer's disease, cardiovascular disease, gene expression, homocysteine, protein modifcation, mTOR signaling, autophagy, epigenetic mechanisms, tRNA synthetase, protein synthesis, error-editing mechanisms, evolutuin of peptide bond sythesis
Biography & Research:
Biography: Hieronim Jakubowski obtained his MSc degree in physical chemistry from the Adam Mickiewicz University Poznań (1969), PhD degree in biochemistry from the Agricultural University, Poznań (1974), and DSc degree in biochemistry from the Institute of Biochemistry and Biophysics, Warsaw (1978).He was a Postdoctoral Fellow at the University of New Mexico, Albuquerque, NM, USA (with Robert B. Loftfield, 1975–1976) and a FEBS Fellow at the Hanover Medical School, Germany (with Günther Maas, Apr - Jul 1982). He was an EMBO Fellow at the Imperial College of Science and Technology, London, UK (with Alan Fersht, Nov - Dec 1980), where he discovered biological synthesis of the thioester homocysteine thiolactone during homocysteine editing by aminoacyl-tRNA synthetases. He took a Yeast Genetics and Molecular Biology Course at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA (Jul 1987–Aug 1987). He received a title of Professor from the President of Poland (Dec 2007). He has made seminal discoveries in the field of tRNA synthetases and error-editing mechanisms in protein biosynthesis, which provided foundation for his more recent discoveries of mechanisms involved in the incorporation of homocysteine into protein, as well as his studies of homocysteine-containing proteins and their role in cardiovascular and neurodegenerative diseases. He is currently an Adjunct Professor of Microbiology, Biochemistry and Molecular Genetics at Rutgers University, New Jersey Medical School, Newark, NJ, USA and a Professor at the Department of Biochemistry and Biotechnology, University of Life Sciences, Poznań. Research: Genetic or nutritional deficiencies in folate/one carbon metabolism cause hyperhomocysteinemia (HHcy) and induce abnormalities in many organs, leading to cardiovascular (CVD) and neurodegenerative diseases, including Alzheimer's (AD). Our main goal is to elucidate mechanisms by which dysregulation of one carbon/Hcy metabolism leads to disease. We found that Hcy is metabolized to the chemically reactive thioester Hcy-thiolactone as a result of an error-editing reaction in protein synthesis catalyzed by methionyl-tRNA synthetase. We also found that Hcy-thiolactone readily modifies protein lysine amino groups to form stable isopeptide bonds (KHcy-protein). This modification alters protein structure/function, causes protein damage, and generates proteins with pro-inflammatory, pro-atherogenic, pro-thrombotic proteins, and pro-amyloid properties. We identified a novel metabolite, KHcy-Lys isopeptide, as a product of proteolytic turnover of KHcy-protein in humans and mice. Recently, in a randomized controlled clinical trial, we found that elevated Hcy-thiolactone is a predictor of acute myocardial infarction in patients with coronary artery disease. We discovered protective mechanisms against Hcy-thiolactone toxicity: hydrolysis by extracellular paraoxonase 1 (PON1) carried in the blood on high-density lipoproteins (HDL, good cholesterol) and by intracellular bleomycin hydrolase in tissues, and urinary elimination by the kidney. Recently we found the third enzyme, BPHL, hydrolyzes Hcy-thiolactone in mice. We also found that PON1 deficiency induces pro-oxidative changes in plasma proteomes, which are exacerbated by HHcy in Pon1-/-mice. We are testing a hypothesis that Hcy-thiolactone and KHcy-protein contribute to CVD and AD. We found that Hcy-thiolactone and KHcy-protein are greatly elevated in genetic or nutritional disorders in Hcy (CBS deficiency) or folate metabolism (MTHFR or PCFT deficiency), that modification with Hcy-thiolactone affects protein structure and physiological activity, and that an autoimmune response to KHcy-protein is associated with stroke and coronary artery disease, and that elevated anti-N-Hcy autoantibodies predict worse cognitive outcomes in individuals with mild cognitive impairment. We also found that HHcy in Cbs-/- mice activates mTORC1 signaling and inhibits autophagy in their brains, which cases accumulation of amyloid beta aggregates and neurodegeneration. Current research: 1) Identification of targets and sites for the Hcy-thiolactone protein modification in humans. 2) The role of an autoimmune response against KHcy-protein in Alzheimer's and CVD. 3) Modulation of the autoimmune response and atherothrombosis by PON1. 4) Examination of epigenetic mechanisms involved in up-regulation of mTOR signaling and inhibition of autophagy by HHcy in mouse models.