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Chemical modification refers to a number of various processes involving the alteration of the chemical constitution or structure of molecules.
| | This article needs additional citations for verification .(December 2009) |
Chemical modification refers to a number of various processes involving the alteration of the chemical constitution or structure of molecules.
Chemical modification is the change of biomolecular structure and function due to the addition or removal of modifying elements. [1] This is usually accomplished via chemical reactions or a series of chemical reactions that may or may not be reversible. Chemical modifications can be done to any of the four major macromolecules (proteins, nucleic acids, carbohydrates, and lipids); however, we will be focusing on the modification of proteins in this article. Chemical modifications are important because they can improve the molecule’s stability, which would increase the stability of the biomolecules and would have a role in allowing the organism to better cope with physiological stressors. [2] Modification of proteins can also introduce the possibility of using them as drugs for possible treatment of a wide range of diseases. Chemical modifiers on compounds that can be used as drugs can also be used to attempt to increase the shelf life of the product or extend its function. [2]
Chemical modification is also another method in which more variability is introduced into the proteome. [1] Chemical modifications of proteins are ever-changing due to the fluctuating needs of the organism. Common chemical modifications include phosphorylation, glycosylation, ubiquitination, methylation, lipidation, and proteolysis. [1] Although we will cover each type of chemical modification singularly, they can often work in conjunction with each other to modify the protein. Due to the large variety of modifications possible, the study of chemical modifications is ongoing.
| Type of Modification | Brief Description: |
|---|---|
| Phosphorylation | Addition or removal of phosphate group (-PO3 ) to a protein. |
| Glycosylation | Addition of a (mono-/di-/poly-) saccharide to a protein. |
| Ubiquination | Addition of a (mono-/poly-) ubiquitin molecule to a protein. Usually used to target for degradation. |
| Methylation | Addition of a methyl (-CH3) group to a protein. |
| Lipidation | Addition of a lipid/fatty acid to a protein. |
| Proteolysis | Enzymes that catalyze the breakdown of other proteins. |
Phosphorylation occurs when a PO3 (phosphoryl) group is added to a protein. [3] This chemical modification is the most extensively studied and is reversible. The result of those studies has shown that phosphorylation acts as a regulator for proteins in two ways: the addition or removal of phosphoryl group can impact enzyme kinetics by turning on or off the enzymatic function via conformational changes and the phosphorylation of one protein can attract neighboring similar proteins to also bind to the phosphorylated motif to induce signal transduction pathways. [1]
The mechanism for phosphorylation utilizes kinases and phosphatases which are enzymes that are used to transfer the phosphoryl group onto and off of the targeted biomolecule. Often, kinases are accompanied by ATP or GTP to help facilitate the transfer of the phosphoryl group. [3] Phosphorylation of a kinase can trigger one of two signal transduction pathways. These pathways may either be linear or a cascade transduction pathway. [4] Cascade signal transduction pathways lead to the phosphorylation of many amino acids and utilize second messengers to amplify the signal to elicit a larger response. [4] Phosphatases can act as a regulator and editor of cellular signaling pathways forming transient protein-protein interactions. [3]
Kinases are most associated with activating enzymatic activity, and phosphatases are most associated with turning off enzymatic activity, they can also perform the opposite function (Kinases can turn off enzymatic activity and Phosphatases can turn off enzymatic activity). Kinases and phosphatases can also have other binding sites that can attach to other signaling proteins. [5]
Phosphorylation and dephosphorylation of proteins through the activity of kinases and phosphatases play an important role in many biological processes such as cell proliferation through the MAPK, PI3K, Akt, mTOR, PKA, and PKC signaling pathway [6] Because over-activation of kinases is associated with cancer progression, drugs that work to inhibit the function of kinases have been developed as possible treatments. [7]
Another well-studied chemical modification is glycosylation. Glycosylation is the process by which sugar molecules are attached to protein. [1] The length of the attached saccharide is variable and impacts the structure, activity, and stability of the protein it is attached to. [8] Many proteins that are glycosylated are often found on cell surfaces and play a large role in determining blood type.
Ubiquitin is made up of 76 amino acids that can exist on its own or attached to a protein. [9] When ubiquitin is attached to a protein (the amount of ubiquitin that binds to the protein varies) it can function to target that protein for degradation or trigger kinase activation. There are three enzymes that function in the ubiquitination pathway: Ubiquitin-activating enzyme (E1), Ubiquitin-conjugating enzyme (E2), and Ubiquitin-protein ligase (E3). [9] Generally, E1 activates ubiquitin and transfers it to E2. E3 transfers ubiquitin to the target protein. [10] This pathway is closely regulated and is very specific. [10] Monoubiquitination (one ubiquitin protein) of a protein does not typically signal for protein degradation, instead it primarily functions to facilitate histone regulation, endocytosis, and nuclear export. [9] Polyubiquination (multiple ubiquitin proteins) of a protein typically triggers protein degradation, especially if they are bound to a lysine residue. [9] The degradation function of ubiquitin is the most well-understood as it has been linked to the NF-𝜿B signaling pathway for triggering inflammation. [9] It has also been implicated as playing a role in cancer and other diseases.
Methylation is the transfer of one methyl group (Carbon atom that is bonded to three Hydrogen atoms) to a protein via enzymes called methyltransferases. [1] It is also often used by histone proteins to allow certain regions of the genome to wind and unwind and become accessible for transcription. [1]
Lipidation is the process of attaching lipids to proteins to tag them as membrane-bound proteins. [1] Different lipid attachments increase the protein’s affinity for different membrane types (plasma membrane, organelle membrane, and vesicles). There are four common types of lipidation: GPI anchors, N-terminal myristoylation, S-myristoylation, and S-prenylation. [1]
Proteolysis is the pathway used to break peptide bonds. Oftentimes, peptide bonds are stable in typical physiological conditions and may need enzymes called proteases to assist in breaking polypeptides into smaller components. [11] This is especially important during cell signaling, removing misfolded proteins, and programmed cell death (apoptosis). [12] In some cases, proteolysis can be used to regulate the enzymatic activity of zymogens (inactive enzymes that require some bonds to be cleaved in order to be activated). [1] There are four main types of proteases: serine proteases, cysteine proteases, aspartic acid proteases, and zinc metalloproteases. [1]
Chemically modified electrodes are electrodes that have their surfaces chemically converted to change the electrode's properties, such as its physical, chemical, electrochemical, optical, electrical, and transport characteristics. These electrodes are used for advanced purposes in research and investigation. [13]
In biochemistry, chemical modification is the technique of anatomically reacting a protein or nucleic acid with a reagent or reagents. Obtaining laboratory information through chemical modification which can be utilized to:
Protein biosynthesis is a core biological process, occurring inside cells, balancing the loss of cellular proteins through the production of new proteins. Proteins perform a number of critical functions as enzymes, structural proteins or hormones. Protein synthesis is a very similar process for both prokaryotes and eukaryotes but there are some distinct differences.
A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a functional change of the target protein (substrate) by changing enzyme activity, cellular location, or association with other proteins. The human genome contains about 500 protein kinase genes and they constitute about 2% of all human genes. There are two main types of protein kinase. The great majority are serine/threonine kinases, which phosphorylate the hydroxyl groups of serines and threonines in their targets. Most of the others are tyrosine kinases, although additional types exist. Protein kinases are also found in bacteria and plants. Up to 30% of all human proteins may be modified by kinase activity, and kinases are known to regulate the majority of cellular pathways, especially those involved in signal transduction.
A protein phosphatase is a phosphatase enzyme that removes a phosphate group from the phosphorylated amino acid residue of its substrate protein. Protein phosphorylation is one of the most common forms of reversible protein posttranslational modification (PTM), with up to 30% of all proteins being phosphorylated at any given time. Protein kinases (PKs) are the effectors of phosphorylation and catalyse the transfer of a γ-phosphate from ATP to specific amino acids on proteins. Several hundred PKs exist in mammals and are classified into distinct super-families. Proteins are phosphorylated predominantly on Ser, Thr and Tyr residues, which account for 79.3, 16.9 and 3.8% respectively of the phosphoproteome, at least in mammals. In contrast, protein phosphatases (PPs) are the primary effectors of dephosphorylation and can be grouped into three main classes based on sequence, structure and catalytic function. The largest class of PPs is the phosphoprotein phosphatase (PPP) family comprising PP1, PP2A, PP2B, PP4, PP5, PP6 and PP7, and the protein phosphatase Mg2+- or Mn2+-dependent (PPM) family, composed primarily of PP2C. The protein Tyr phosphatase (PTP) super-family forms the second group, and the aspartate-based protein phosphatases the third. The protein pseudophosphatases form part of the larger phosphatase family, and in most cases are thought to be catalytically inert, instead functioning as phosphate-binding proteins, integrators of signalling or subcellular traps. Examples of membrane-spanning protein phosphatases containing both active (phosphatase) and inactive (pseudophosphatase) domains linked in tandem are known, conceptually similar to the kinase and pseudokinase domain polypeptide structure of the JAK pseudokinases. A complete comparative analysis of human phosphatases and pseudophosphatases has been completed by Manning and colleagues, forming a companion piece to the ground-breaking analysis of the human kinome, which encodes the complete set of ~536 human protein kinases.
In biochemistry, a kinase is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule donates a phosphate group to the substrate molecule. As a result, kinase produces a phosphorylated substrate and ADP. Conversely, it is referred to as dephosphorylation when the phosphorylated substrate donates a phosphate group and ADP gains a phosphate group. These two processes, phosphorylation and dephosphorylation, occur four times during glycolysis.
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule in order to form a glycoconjugate. In biology, glycosylation usually refers to an enzyme-catalysed reaction, whereas glycation may refer to a non-enzymatic reaction.
The JAK-STAT signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death, and tumour formation. The pathway communicates information from chemical signals outside of a cell to the cell nucleus, resulting in the activation of genes through the process of transcription. There are three key parts of JAK-STAT signalling: Janus kinases (JAKs), signal transducer and activator of transcription proteins (STATs), and receptors. Disrupted JAK-STAT signalling may lead to a variety of diseases, such as skin conditions, cancers, and disorders affecting the immune system.
In biochemistry, dephosphorylation is the removal of a phosphate (PO43−) group from an organic compound by hydrolysis. It is a reversible post-translational modification. Dephosphorylation and its counterpart, phosphorylation, activate and deactivate enzymes by detaching or attaching phosphoric esters and anhydrides. A notable occurrence of dephosphorylation is the conversion of ATP to ADP and inorganic phosphate.
A regulatory enzyme is an enzyme in a biochemical pathway which, through its responses to the presence of certain other biomolecules, regulates the pathway activity. This is usually done for pathways whose products may be needed in different amounts at different times, such as hormone production. Regulatory enzymes exist at high concentrations so their activity can be increased or decreased with changes in substrate concentrations
Deubiquitinating enzymes (DUBs), also known as deubiquitinating peptidases, deubiquitinating isopeptidases, deubiquitinases, ubiquitin proteases, ubiquitin hydrolases, or ubiquitin isopeptidases, are a large group of proteases that cleave ubiquitin from proteins. Ubiquitin is attached to proteins in order to regulate the degradation of proteins via the proteasome and lysosome; coordinate the cellular localisation of proteins; activate and inactivate proteins; and modulate protein-protein interactions. DUBs can reverse these effects by cleaving the peptide or isopeptide bond between ubiquitin and its substrate protein. In humans there are nearly 100 DUB genes, which can be classified into two main classes: cysteine proteases and metalloproteases. The cysteine proteases comprise ubiquitin-specific proteases (USPs), ubiquitin C-terminal hydrolases (UCHs), Machado-Josephin domain proteases (MJDs) and ovarian tumour proteases (OTU). The metalloprotease group contains only the Jab1/Mov34/Mpr1 Pad1 N-terminal+ (MPN+) (JAMM) domain proteases.
In biology, cell signaling is the process by which a cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all cellular life in prokaryotes and eukaryotes.
Lipid signaling, broadly defined, refers to any biological cell signaling event involving a lipid messenger that binds a protein target, such as a receptor, kinase or phosphatase, which in turn mediate the effects of these lipids on specific cellular responses. Lipid signaling is thought to be qualitatively different from other classical signaling paradigms because lipids can freely diffuse through membranes. One consequence of this is that lipid messengers cannot be stored in vesicles prior to release and so are often biosynthesized "on demand" at their intended site of action. As such, many lipid signaling molecules cannot circulate freely in solution but, rather, exist bound to special carrier proteins in serum.
Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. The receptors are generally activated by dimerization and substrate presentation. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non-receptor tyrosine kinases which do not possess transmembrane domains.
Protein phosphorylation is a reversible post-translational modification of proteins in which an amino acid residue is phosphorylated by a protein kinase by the addition of a covalently bound phosphate group. Phosphorylation alters the structural conformation of a protein, causing it to become activated, deactivated, or otherwise modifying its function. Approximately 13,000 human proteins have sites that are phosphorylated.
The Akt signaling pathway or PI3K-Akt signaling pathway is a signal transduction pathway that promotes survival and growth in response to extracellular signals. Key proteins involved are PI3K and Akt.
A non-receptor tyrosine kinase (nRTK) is a cytosolic enzyme that is responsible for catalysing the transfer of a phosphate group from a nucleoside triphosphate donor, such as ATP, to tyrosine residues in proteins. Non-receptor tyrosine kinases are a subgroup of protein family tyrosine kinases, enzymes that can transfer the phosphate group from ATP to a tyrosine residue of a protein (phosphorylation). These enzymes regulate many cellular functions by switching on or switching off other enzymes in a cell.
Cell surface receptors are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving extracellular molecules. They are specialized integral membrane proteins that allow communication between the cell and the extracellular space. The extracellular molecules may be hormones, neurotransmitters, cytokines, growth factors, cell adhesion molecules, or nutrients; they react with the receptor to induce changes in the metabolism and activity of a cell. In the process of signal transduction, ligand binding affects a cascading chemical change through the cell membrane.
The insulin transduction pathway is a biochemical pathway by which insulin increases the uptake of glucose into fat and muscle cells and reduces the synthesis of glucose in the liver and hence is involved in maintaining glucose homeostasis. This pathway is also influenced by fed versus fasting states, stress levels, and a variety of other hormones.
Tyrosine phosphorylation is the addition of a phosphate (PO43−) group to the amino acid tyrosine on a protein. It is one of the main types of protein phosphorylation. This transfer is made possible through enzymes called tyrosine kinases. Tyrosine phosphorylation is a key step in signal transduction and the regulation of enzymatic activity.
O-GlcNAc is a reversible enzymatic post-translational modification that is found on serine and threonine residues of nucleocytoplasmic proteins. The modification is characterized by a β-glycosidic bond between the hydroxyl group of serine or threonine side chains and N-acetylglucosamine (GlcNAc). O-GlcNAc differs from other forms of protein glycosylation: (i) O-GlcNAc is not elongated or modified to form more complex glycan structures, (ii) O-GlcNAc is almost exclusively found on nuclear and cytoplasmic proteins rather than membrane proteins and secretory proteins, and (iii) O-GlcNAc is a highly dynamic modification that turns over more rapidly than the proteins which it modifies. O-GlcNAc is conserved across metazoans.