Posttranslational protein modifications.

There are 300 different protein posttranslational modifications (PTMs), which include such diverse processes as proteolysis, phosphorylation, lipidation, S-nitrosylation, nitration, oxidation, glycosylation, methylation, adenosine diphosphate (ADP)-ribosylation, acylation (acetylation, isoprenylation, myristoylation), ubiquitination, sumoylation, sulfation, farnesylation, and many, many others (1). PTMs change the size, charge, structure and conformation of proteins. As a result, characteristics of proteins, such as enzyme activity, binding affinity, and protein hydrophobicity, are altered. PTMs cannot only directly change the proteins’ function but also indirectly affect function by leading to cell compartmentalization, sequestration, degradation, elimination, and protein–protein interactions (Fig. 1). Individual proteins can undergo multiple and different PTMs. The discovery of PTMs likely dates back to some time shortly after the discovery of proteins because proteolysis can be considered a PTM. Proteases belong to several families, categorized based on their amino acid target sites. Common examples important in critical illness include the serine and cysteine proteases. For example, thrombin is a serine protease (2). The caspase family of cysteine proteases includes caspase-1, also known as interleukin-1 – converting enzyme, and caspase-3, the latter a key component in apoptotic cell death (3). Caspase-3, which requires proteolysis itself to facilitate formation of the active tetrameric enzyme complex, has been shown to be activated in patients with sepsis (4) and traumatic brain injury (3). Other representative PTMs, and their relevance to critical illness, are discussed below.