Hieronim Jakubowski, Ph.D.
Homocysteine (Hcy) excess of is harmful to humans and is associated with increased risk of cardiovascular and neurodegenerative diseases. 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 (N-Hcy-protein). This modification reaction alters protein structure and function, causes protein damage, and leads to pathological consequences such as an autoimmune response, thrombosis, and elastic tissue defects.
We are interested in elucidating mechanisms underlying Hcy role in human disease. We are exploring a hypothesis that N-Hcy-proteins contribute to human pathology. We found that N-Hcy-proteins 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 N-Hcy-protein is associated with stroke and coronary artery disease. We also found that proteolytic turnover of N-Hcy-protein in humans and mice yields N-Hcy-Lys isopeptide. We discovered protective mechanisms against Hcy-thiolactone toxicity in humans: hydrolysis by extracellular PON1/Hcy-thiolactonase carried on high-density lipoproteins (HDL, good cholesterol) in the blood and by intracellular bleomycin hydrolase/Hcy-thiolactone in tissues, and urinary elimination by the kidney.
Current research: 1. Identification of proteins targets for the modification by Hcy-thiolactone and determination of site-specific N-homocysteinylation in vivo in humans. 2. The pro-thrombotic role of N-Hcy-fibrinogen in CBS-deficient patients and mice. 4. The role of an autoimmune response against N-Hcy-protein in thrombosis. 5. Modulation of an autoimmune response and thrombosis by PON1/Hcy-thiolactonase in CBS-deficient patients. 6. The role of N-homocysteinylation in elastin fiber maturation in mouse models (Cbs-KO, Mthfr-KO, and Pcft-KO). .
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