Amino Acids

, Volume 44, Issue 5, pp 1307–1316

S-linked protein homocysteinylation: identifying targets based on structural, physicochemical and protein–protein interactions of homocysteinylated proteins

  • Yumnam Silla
  • Elayanambi Sundaramoorthy
  • Puneet Talwar
  • Shantanu Sengupta
Original Article


An elevated level of homocysteine, a thiol-containing amino acid is associated with a wide spectrum of disease conditions. A majority (>80 %) of the circulating homocysteine exist in protein-bound form. Homocysteine can bind to free cysteine residues in the protein or could cleave accessible cysteine disulfide bonds via thiol disulfide exchange reaction. Binding of homocysteine to proteins could potentially alter the structure and/or function of the protein. To date only 21 proteins have been experimentally shown to bind homocysteine. In this study we attempted to identify other proteins that could potentially bind to homocysteine based on the criteria that such proteins will have significant 3D structural homology with the proteins that have been experimentally validated and have solvent accessible cysteine residues either with high dihedral strain energy (for cysteine–cysteine disulfide bonds) or low pKa (for free cysteine residues). This analysis led us to the identification of 78 such proteins of which 68 proteins had 154 solvent accessible disulfide cysteine pairs with high dihedral strain energy and 10 proteins had free cysteine residues with low pKa that could potentially bind to homocysteine. Further, protein–protein interaction network was built to identify the interacting partners of these putative homocysteine binding proteins. We found that the 21 experimentally validated proteins had 174 interacting partners while the 78 proteins identified in our analysis had 445 first interacting partners. These proteins are mainly involved in biological activities such as complement and coagulation pathway, focal adhesion, ECM-receptor, ErbB signalling and cancer pathways, etc. paralleling the disease-specific attributes associated with hyperhomocysteinemia.


Homocysteine Homologous structure Disulfide Dihedral strain energy pKa Protein–protein interaction 





Dihedral strain energy


Dictionary of secondary structure prediction


Protein–protein interaction


Database for annotation, visualization and integrated discovery


Gene ontology


Cellular compartment


Biological process


Molecular function

Supplementary material

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Supplementary material 1 (PDF 864 kb)
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Supplementary material 2 (PDF 301 kb)
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Supplementary material 3 (PDF 227 kb)
726_2013_1465_MOESM4_ESM.pdf (8 kb)
Supplementary material 4 (PDF 8 kb)
726_2013_1465_MOESM5_ESM.pdf (85 kb)
Supplementary material 5 (PDF 85 kb)


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Copyright information

© Springer-Verlag Wien 2013

Authors and Affiliations

  • Yumnam Silla
    • 1
  • Elayanambi Sundaramoorthy
    • 1
    • 2
  • Puneet Talwar
    • 1
  • Shantanu Sengupta
    • 1
  1. 1.CSIR-Institute of Genomics and Integrative BiologyDelhiIndia
  2. 2.Department of Oncology, Medical Research Council, Cancer Cell Unit Hutchison/MRC Research CentreUniversity of CambridgeCambridgeUK

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