Regulation by Covalent Modification


Covalent modifications are enzyme‐catalysed alterations of synthesised proteins and include the addition or removal of chemical groups. Modifications can target a single type of amino acid or multiple amino acids and will change the chemical properties of the site. Consequences on the structure and functions of the protein modified are manifested providing a sensitive method for cellular regulation. The modification of the protein can be reversible or irreversible; in most instances, there are different enzymes responsible for the forward and reverse reactions. Reversible modifications typically associated with the regulation of signalling and metabolic processes and select critical targets can be modified by multiple types of modifications at multiple types of amino acids with multiple number of modifications. Irreversible modifications are more energetically costly requiring the synthesis of new protein before the functional modification can be accomplished if needed.

Key Concepts:

  • Select enzymes catalyse the transfer of a chemical group from a donor to a target protein.

  • The target protein is modified on a specific amino acid consistent with the chemistry of the modifying group.

  • Modifications can influence the properties of the target protein with changes in structure, charge and function.

  • Enzyme‐catalysed modifications can be reversible or irreversible; reversible modifications typically require different enzymes for the reverse reaction.

  • Reversible modifications typically associated with regulatory processes or in regulatory steps of metabolic and signalling pathways.

  • Select critical processes and proteins are targets of multiple types and sites of reversible modifications.

  • Irreversible modifications require the synthesis of protein.

  • Irreversible modifications typically associated with physiological cascade processes such as blood coagulation.

Keywords: co‐translation modification; post‐translational modification

Figure 1.

Generalised scheme for covalent modification reactions. Shown is an example of a transfer of a generic group (X) to a specific acceptor residue (A) on the target protein. The site (A) becomes modified. In other reactions, cleavage for example, a group may be removed from the target site (A).



Arnesen T (2011) Towards a functional understanding of protein N‐terminal acetylation. PLoS Biology 9: e1001074.

Caldecott KW (2014) Protein ADP‐ribosylation and the cellular response to DNA strand breaks. DNA Repair. doi:10.1016/j.dnarep.2014.03.021.

Fernandes RJ, Farnand AW, Traeger GR, Weis MA and Eyre DR (2011) A role for prolyl 3‐hydroxylase 2 in post‐translational modification of fibril‐forming collagens. Journal of Biological Chemistry 286: 30662–30669.

Goody RS and Itzen A (2013) Modulation of small GTPases by legionella. Current Topics in Microbiology and Immunology 376: 117–133.

Gorres KL and Raines RT (2010) Prolyl 4‐hydroxylase. Critical Reviews in Biochemistry and Molecular Biology 45: 106–124.

Itzen A, Blankenfeldt W and Goody RS (2011) Adenylylation: renaissance of a forgotten post‐translational modification. Trends in Biochemical Science 36: 221–228.

Li N and Chen J (2014) ADP‐ribosylation: activation, recognition, and removal. Molecules and Cells 30: 9–16.

Ludeman JP and Stone MJ (2014) The structural role of receptor tyrosine sulfation in chemokine recognition. British Journal of Pharmacolcology 171: 1167–1179.

Pereira SF, Goss L and Dworkin J (2011) Eukaryote‐like serine/threonine kinases and phosphatases in bacteria. Microbiology and Molecular Biology Reviews 75: 192–212.

Rajala RVS (2005) How does the biological function of N‐myristoylation differ from that of N‐palmitoylation? IUBMB Life 57: 597–598.

Sebti SM (2005) Protein farnesylation: implications for normal physiology, malignant transformation, and cancer therapy. Cancer Cell 7: 297–300.

Seibert C and Sakmar TP (2008) Toward a framework for sulfoproteomics: synthesis and characterization of sulfotyrosine‐containing peptides. Biopolymers 90: 459–477.

Shall S and Sugimura T (2005) What is new about ADP‐ribosylation? Bioessays 28: 97–99.

Stewart RC (2010) Protein histidine kinases: assembly of active sites and their regulation in signaling pathways. Current Opinion in Microbiology 13: 133–141.

Sun L and Chen ZJ (2004) The novel functions of ubiquitination in signaling. Current Opinion in Cell Biology 16: 119–126.

van Wijk SJL and Timmers HTM (2010) The family of ubiquitin‐conjugating enzymes (E2s): deciding between life and death of proteins. FASEB Journal 24: 981–993.

Woo CH1 and Abe J (2010) SUMO – a post‐translational modification with therapeutic potential? Current Opinion in Pharmacology 10: 146–155.

Yang X‐J (2004) Lysine acetylation and the bromodomain: a new partnership for signaling. Bioessays 26: 1076–1087.

Further Reading

Chock PB, Rhee SG and Stadtman ER (1980) Interconvertible enzyme cascades in cellular regulation. Annual Review of Biochemistry 49: 813–843.

Graves DJ, Martin BL and Wang JH (1994) Co‐ and Post‐translational Modification of Proteins. New York, NY: Oxford University Press.

Martin BL (1995) Enzymology of co‐ and post‐translational modifications of proteins. In: Meyers RA (ed.) Encyclopedia of Molecular Biology, vol. 5, pp. 49–56. Weinheim: VCH Publishers.

Parekh R and Rohlff C (1997) Post‐translational modification of proteins and the discovery of new medicine. Current Opinion in Biotechnology 8: 718–723.

Resh MD (2012) Targeting protein lipidation in disease. Trends in Molecular Medicine 18: 206–214

Seo J and Lee K‐J (2004) Post‐translational modifications and their biological functions: proteomic analysis and systematic approaches. Journal of Biochemistry and Molecular Biology 37: 35–44.

Uy R and Wold F (1977) Posttranslational covalent modification of proteins. Science 198: 890–896.

Wold F (1981) In vivo chemical modification of proteins (post‐translational modification). Annual Review of Biochemistry 50: 783–814.

Wold F and Moldave K (eds) (1984) Methods in Enzymology, vol. 106–107. New York, NY: Academic Press.

Zverina EA, Lamphear CL, Wright EN and Fierke CA (2012) Recent advances in protein prenyltransferases: substrate identification, regulation, and disease interventions. Current Opinion in Chemical Biology 16: 544–552.

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Martin, Bruce L(Aug 2014) Regulation by Covalent Modification. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000866.pub3]