DEPARTMENT OF BIOCHEMISTRY

Research group of prof. Ljuba M. Mandić

Research description:

α-Oxoaldehydes, produced in higher quantities in diabetes, uremia, oxidative stress, inflammation and aging, react with proteins amino and guanidine groups and cause the formation of advanced glycated end-products (AGEs). Molecules modified with α-oxoaldehydes can affect cellular functionality via gene expression, lead to micro- and macro-vascular complications in diabetes, and contribute to upregulation of inflammatory and tissue-injury-provoking molecules (interaction of AGEs and receptor RAGE), protein cross-linking and apoptosis. The role of thiol group in protein modification with α-oxoaldehyde as well as in cross-linking via reactive compounds has not been sufficiently investigated. The final products of these reactions are not well-characterized as well as the consequences that may occur due to changes in structure and function of proteins. Also, the possibilities for their usage as markers of pathological states and how to prevent modification should be consider. Therefore main topics of our research are:

• Carbonylation of protein thiol group. Carbonylation of human serum albumin (HSA) Cys34 thiol group with methylglyoxal: kinetic, chemical and structural changes and their contribution to protein functions changes, and formation of AGEs.
• HSA Cys34-SH group reactivity and antioxidant properties: influence of fatty acids binding to HSA on the thiol group reactivity; reactivity changes in various diseases; modulation of HSA antioxidant properties.
• Cu/HSA redox potential and prooxidative properties of HSA in vitro and in vivo: influence of Cys34 carbonylation and fatty acid binding, in different diseases with carbonyl and/or oxidative stress.
• Protein carbonylation reaction products and possibilities for their determination and application in clinical and toxicological practice. Protein carbonylation is a well-used marker for oxidative stress. Assessment of protein-SH group content as a suitable parameter for oxidative and/or carbonyl stress level in different pathological states.
• Compounds acting as scavengers of reactive carbonyl species (identified as the chemical intermediates between hyperglycemia, hyperlipidemia, and their complications). Development of agents, which can control cellular protein carbonylation in various diseases: efficiency of low molecular mass thiols with α-amino-β-mercapto-ethane group as protective agents of carbonylation of protein amino, guanidine and thiol groups.

In addition, research of the group is focused on investigation of anticholinesterase activity of compounds based on aroylacrylic acid scaffold: invstigation of 4-aryl-4-oxo-2-(N-aryl/cycloalkyl)butyramides activities toward biological targets relevant for Alzheimers disease and for the control of Dermanyssus gallinae.

Selected recent publications:

1. V. B. Jovanović, A. Z. Penezić-Romanjuk, I. D. Pavićević, J. M. Aćimović, Lj. M. Mandić, (2014) The influence of fatty acids on determination of human serum albumin thiol group. Analytical Biochemistry, 448, 50-57
2. Jelena M. Acimovic; Vesna B. Jovanovic; Vesna Dimitrijevic Sreckovic; Ana Penezic-Romanjuk and Ljuba M. Mandic, (2013) Monitoring of the human serum albumin carbonylation level through determination of guanidino group content. Analytical Biochemistry 433, 162-167
3. V. B. Jovanović, A. Z. Penezić-Romanjuk, I. D. Pavićević, J. M. Aćimović, Lj. M. Mandić, (2013) Improving the reliability of human serum albumin-thiol group determination. Analytical Biochemistry 439, 17-22
4. Tamara Popović, Suncica Borozan, Ljuba Mandić, Aleksandra Arsić, Jasmina Debeljak Martačić, Vesna Vučić, Aleksandar Trbović, Marija Glibetić (2012) Fish oil supplementation improved liver phospholipids fatty acid composition and parameters of oxidative stress in male Wistar rats. Journal of Animal Physiology and Animal Nutrition 96(6), 1020-1029
5. Jelena M. Acimovic; Vesna B. Jovanovic; Milica R. Veselinovic; Vesna Dimitrijevic Sreckovic; Ljuba M. Mandic (2011) Method for monitoring of the protein amino group changes during carbonylation. Clin. Biochem. 44, 994-999
6. Jelena M. Acimović, Bojana D. Stanimirović, Nina Todorović, Vesna B. Jovanović, Ljuba M. Mandić (2010) Influence of the microenvironment of thiol groups in low molecular mass thiols and serum albumin on the reaction with methylglyoxal. Chemico-Biological Interactions 188, 21-30
7. Jelena Aćimović, Bojana Stanimirović, Ljuba Mandić (2009) The role of thiol group in protein modification with methylglyoxal. Journal of Serbian Chemical Society 74 (8-9), 867-883
8. Marija Takic, Danijela K Ristic-Medic, Ljuba M Mandic, Marija Glibetic, Aleksandra Arsic, Jasmina Debeljak-Martacic, Gordana Ristic-Oddiano (2009) N-3 polyunsaturated acids in erythrocyte phospholipids are associated with insulin sensitivity in obese patients on a typical Serbian diet. Archives of biological sciences 61 (1), 37-43
9. Maja D. Vitorović-Todorović, Catherine Koukoulitsa, Ivan O. Juranić, Ljuba M. Mandić, Branko J. Drakulić (2014) Structural modifications of 4-aryl-4-oxo-2-aminylbutanamides and their acetyl- and butyrylcholinesterase inhibitory activity. Investigation of AChE-ligand interactions by docking calculations and molecular dynamics simulations. European Journal of Medicinal Chemistry 81, 158-175.
10. Vesna P. Stankov-Jovanović, Violeta D. Mitić, Marija D. Ilić, Ljuba M. Mandić, Snežana D. Nikolić-Mandić, (2012) Enzymatic kinetic method for determination of propranolol hydrochloride in pharmaceuticals based on its inhibitory effect on cholinesterase. Chemical Industry 66 (5) , 677-684