Overview
Dr. Jakubowski obtained his MSc degree in physical chemistry from the Adam Mickiewicz University,
Poznan (1969), PhD degree in biochemistry from the Agricultural University, Poznan (1974), and DSc
degree in biochemistry from the Institute of Biochemistry and Biophysics, Warsaw (1978). He was a
post-doc at UNM, Albuquerque, NM (1975-76), an EMBO Fellow at the Imperial College Sci Tech,
London, UK (1980), and a FEBS Fellow at the Hanover Med Sch, Germany (1982). He took an
YGMB Course at the Cold Spring Harbor Laboratory, NY (1987). He joined the NJMS in 1982.He
received his Professor of Chemistry nomination (2008) and Gold Cross of Merit (2021) from the
President of Poland.
Dr. Jakubowski is recognized internationally for his work on the fidelity and error-editing mechanisms
of aminoacyl-tRNA synthetases, the origin of coded peptide synthesis, protein-related Hcy
metabolism and its role in human heart and brain diseases.
Dr. Jakubowski served/serves as a scientific consultant on numerous federal and private grant study
sections, including NIH, Am Cancer Soc, AHA, NSF, Am Chem Soc, US Army Res Office, VA, and
research funding agencies in Europe. He serves on Editorial Boards of Amino Acids (Springer),
Biomed Pharmacother, J Alzheimer's Dis, IJMS, Int J Genomics, Sci Rep, Life. He has authored over
190 scientific publications, including a book.
Dr. Jakubowski is an Adjunct Professor at Rutgers-NJMS and a Professor at Poznan
University of Life Scien
Education
DSC, 1978, Inst. Of Biochemistry, Polish Academy of Sciences, Warsaw, Poland
DSc, 1978, Inst. Of Biochemistry, Polish Academy of Sciences, Warsaw, Poland
PHD, 1973, Agricultural University, Poznan, Poland
MSC, 1969, Adam Mickiewicz University, Poznan, Poland
Curriculum Vitae
View CV
Homocysteine in Protein Structure/Function and Human Disease
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). However, the underlying mechanisms are not fully understood. We found that Hcy is metabolized to the chemically reactive thioester Hcy-thiolactone in 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) (Figure 1). This modification alters protein
structure/function, causes protein damage, and generates amyloid-like proteins with pro-inflammatory, pro-atherogenic, and pro-thrombotic proteins. In a recent 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.
We are interested in elucidating mechanisms underlying the role of protein-related Hcy metabolism in human disease. 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 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. We identified a novel metabolite, KHcy-Lys isopeptide, which is a product of the proteolytic turnover of KHcy-protein in humans and mice. We also found that HHcy in Cbs-/- mice upregulates mTORC1
signaling and inhibits autophagy in their brains, which leads to the accumulation of Abeta aggregates and neurodegeneration.
Current research: 1. A role of an autoimmune response against KHcy-protein in the development of AD and CVD. 2. Modulation of the autoimmune response and atherothrombosis by Hcy-thiolactone-hydrolyzing enzymes (PON1, BLMH) in AD and CVD . 3. Mechanistic studies of epigenetic dysregulation of mTOR signaling and autophagy by HHcy in AD mouse models and cell cultures.
Figure 1. Biological pathway leading to KHcy-protein modification in humans. (A) Hcy editing by methionyl-tRNA synthetase (MARS). (B) Protein N-hcomocysteinylation by Hcy-thiolactone.
