Introduction

After a protein is synthesized from messenger RNA via translation, it often undergoes post-translational
modifications (PTMs) before becoming functional. PTMs are important biochemical processes that alter
proteins after they are translated and are essential for proper protein function, regulation and turnover.
Some common types of PTMs include phosphorylation, acetylation, glycosylation, ubiquitination,
sumoylation and methylation. PTMs play critical roles in regulating various cellular pathways and
biological processes.

Types of Post-translational Modifications

Phosphorylation

Phosphorylation involves the addition of a phosphate group to serine, threonine or tyrosine amino acid
residues on a protein by protein kinases. It is one of the most common and important PTMs.
Phosphorylation alters protein conformation and activity, allowing regulation of enzyme activity, protein-
protein interactions and subcellular localization. Dysregulated phosphorylation is associated with
diseases.

Acetylation

Acetylation occurs through the addition of an acetyl group to lysine residues. It plays roles in gene
expression regulation, chromatin remodeling and protein stability. Dysregulation of histone acetylation is
linked to cancer. Lysine acetylation of proteins such as tubulin also affects cellular processes.

Glycosylation

Glycosylation is the attachment of carbohydrate chains known as glycans to asparagine, serine or

threonine residues. It influences protein folding, stability, intracellular trafficking and receptor functions.
Glycosylation abnormalities cause diseases.

Ubiquitination

Ubiquitin is attached to lysine residues via an enzymatic cascade. Ubiquitination marks proteins for
degradation by the proteasome and also impacts endocytosis, DNA repair and signaling. Malfunctions
cause cancer and neurodegeneration.

Sumoylation
SUMO (small ubiquitin-like modifier) proteins are attached to lysine residues in a similar pathway as
ubiquitination. Sumoylation regulates processes like nuclear-cytosolic transport, transcriptional
regulation, apoptosis and response to stress. It is implicated in cancer, neurological disorders and
cardiovascular diseases.

Methylation

Methylation adds a methyl group to arginine or lysine residues. Arginine methylation controls pre-mRNA
splicing and protein-protein interactions. Lysine methylation regulates gene expression through histone
modifications. Abnormalities cause diseases.

Other PTMs include nitrosylation, citrullination, ADP-ribosylation and formation of disulfide bonds.
These fine-tune protein structure and diversify proteomes.

Functions and Regulation of PTMs

PTMs exert control over various cellular pathways:

Signaling pathways - Phosphorylation relays signals through mitogen-activated protein kinases, Wnt,
TGF-beta pathways etc.

Gene expression - Acetylation, methylation and ubiquitination modify histones to control chromatin
structure and transcription.

Metabolic regulation - Phosphorylation regulates enzymes of carbon, lipid and nitrogen metabolic
pathways.

Apoptosis - Ubiquitination and sumoylation mediate programmed cell death.

DNA repair - Ubiquitin and sumoylation tags proteins involved in base excision and mismatch repair.

Cell cycle - Phosphorylation drives transitions between cycle phases through cyclin-CDK complexes.
PTM levels are dynamically regulated by enzymes. Protein kinases and phosphatases add and remove
phosphate groups. Acetyltransferases and deacetylases control acetylation state. The entire PTM
network is tightly orchestrated and imbalances lead to disease states. Specific kinases and phosphatases
emerge as drug targets.

Tools to Study PTMs

Mass spectrometry based proteomics enables large-scale identification and quantification of PTMs
across tissues and disease states. Antibodies are used to monitor levels and sites of individual PTMs.
Protein microarrays profile substrate specificities of PTM enzymes. Fluorescent tags allow visualization of
PTMs in live cells. Genome-wide screens identify new PTM enzymes and substrates. Integrative
approaches combine different Omics datasets to understand systemic PTM regulation. These tools
advance our understanding of PTM functions in health and disease.

Roles in Diseases

Aberrant PTMs participate in disease pathogenesis:

Cancer - Oncogenic mutations dysregulate key phosphorylation and acetylation enzymes.

Neurodegeneration - Phosphorylation, ubiquitination and acetylation tags implicated in Alzheimer's and

Parkinson's.

Inflammation - Nitration and citrullination contribute to conditions like arthritis.

Diabetes - Hyperglycemia enhances protein glycation and nitration.

Aging - Gradual loss of protein homeostasis linked to altered PTMs.

Understanding disease-specific PTM signatures helps discover biomarkers and drug targets. Therapeutics
focus on selective modulation of phosphorylation, ubiquitination and other disease-related PTMs.
Conclusion

In summary, post-translational modifications expand the functional diversity and regulation of the
proteome through reversible, covalent attachment of chemical groups. Precisely controlled by enzyme
networks, PTMs impact all fundamental cell processes and pathways. Dysregulation of PTMs underlies
many diseases by perturbing normal signaling, expression and homeostasis. Continued interrogation of
PTM dynamics expands our fundamental knowledge and drives therapeutic strategies targeting aberrant
modifications in illness.