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Trade names | Halocur |
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Chemical and physical data | |
Formula | C16H17BrClN3O3 |
Molar mass | 414.68 g·mol−1 |
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Halofuginone, sold under the brand name Halocur, is a coccidiostat used in veterinary medicine. It is a synthetic halogenated derivative of febrifugine, a natural quinazolinone alkaloid which can be found in the Chinese herb Dichroa febrifuga (Chang Shan). [1] Collgard Biopharmaceuticals is developing halofuginone for the treatment of scleroderma and it has received orphan drug designation from the U.S. Food and Drug Administration. [2]
Halofuginone inhibits the development of T helper 17 cells, immune cells that play an important role in autoimmune disease, but it does not affect other kinds of T cells which are involved in normal immune function. [3] Halofuginone therefore has potential for the treatment of autoimmune disorders. [4]
Halofuginone is also an inhibitor of collagen type I gene expression and as a consequence it may inhibit tumor cell growth. [1] Halofuginone exerts its effects by acting as a high affinity inhibitor of the enzyme glutamyl-prolyl tRNA synthetase. Inhibition of prolyl tRNA charging leads to the accumulation of uncharged prolyl tRNAs, which serve as a signal to initiate the amino acid starvation response, which in turn exerts anti-inflammatory and anti-fibrotic effects. [5]
The genetic code is the set of rules used by living cells to translate information encoded within genetic material into proteins. Translation is accomplished by the ribosome, which links proteinogenic amino acids in an order specified by messenger RNA (mRNA), using transfer RNA (tRNA) molecules to carry amino acids and to read the mRNA three nucleotides at a time. The genetic code is highly similar among all organisms and can be expressed in a simple table with 64 entries.
Pyrrolysine is an α-amino acid that is used in the biosynthesis of proteins in some methanogenic archaea and bacteria; it is not present in humans. It contains an α-amino group, a carboxylic acid group. Its pyrroline side-chain is similar to that of lysine in being basic and positively charged at neutral pH.
Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent activity of the immune system.
An aminoacyl-tRNA synthetase, also called tRNA-ligase, is an enzyme that attaches the appropriate amino acid onto its corresponding tRNA. It does so by catalyzing the transesterification of a specific cognate amino acid or its precursor to one of all its compatible cognate tRNAs to form an aminoacyl-tRNA. In humans, the 20 different types of aa-tRNA are made by the 20 different aminoacyl-tRNA synthetases, one for each amino acid of the genetic code.
Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreases in available oxygen in the cellular environment, or hypoxia. They are only present in parahoxozoan animals.
Activation, in chemistry and biology, is the process whereby something is prepared or excited for a subsequent reaction.
The stringent response, also called stringent control, is a stress response of bacteria and plant chloroplasts in reaction to amino-acid starvation, fatty acid limitation, iron limitation, heat shock and other stress conditions. The stringent response is signaled by the alarmone (p)ppGpp, and modulates transcription of up to 1/3 of all genes in the cell. This in turn causes the cell to divert resources away from growth and division and toward amino acid synthesis in order to promote survival until nutrient conditions improve.
Aminoacyl-tRNA is tRNA to which its cognate amino acid is chemically bonded (charged). The aa-tRNA, along with particular elongation factors, deliver the amino acid to the ribosome for incorporation into the polypeptide chain that is being produced during translation.
Opiorphin is an endogenous chemical compound first isolated from human saliva. Initial research with mice shows the compound has a painkilling effect greater than that of morphine. It works by stopping the normal breakup of enkephalins, natural pain-killing opioids in the spinal cord. It is a relatively simple molecule consisting of a five-amino acid polypeptide, Gln-Arg-Phe-Ser-Arg (QRFSR).
Purine metabolism refers to the metabolic pathways to synthesize and break down purines that are present in many organisms.
Asparagine synthetase is a chiefly cytoplasmic enzyme that generates asparagine from aspartate. This amidation reaction is similar to that promoted by glutamine synthetase. The enzyme is ubiquitous in its distribution in mammalian organs, but basal expression is relatively low in tissues other than the exocrine pancreas.
Procollagen-proline dioxygenase, commonly known as prolyl hydroxylase, is a member of the class of enzymes known as alpha-ketoglutarate-dependent hydroxylases. These enzymes catalyze the incorporation of oxygen into organic substrates through a mechanism that requires alpha-Ketoglutaric acid, Fe2+, and ascorbate. This particular enzyme catalyzes the formation of (2S, 4R)-4-hydroxyproline, a compound that represents the most prevalent post-translational modification in the human proteome.
Bifunctional aminoacyl-tRNA synthetase is an enzyme that in humans is encoded by the EPRS gene.
Dichroa febrifuga is a flowering plant in the family Hydrangeaceae.
Scleroderma is a group of autoimmune diseases that may result in changes to the skin, blood vessels, muscles, and internal organs. The disease can be either localized to the skin or involve other organs, as well. Symptoms may include areas of thickened skin, stiffness, feeling tired, and poor blood flow to the fingers or toes with cold exposure. One form of the condition, known as CREST syndrome, classically results in calcium deposits, Raynaud's syndrome, esophageal problems, thickening of the skin of the fingers and toes, and areas of small, dilated blood vessels.
Amino acid activation refers to the attachment of an amino acid to its respective transfer RNA (tRNA). The reaction occurs in the cell cytosol and consists of two steps: first, the enzyme aminoacyl tRNA synthetase catalyzes the binding of adenosine triphosphate (ATP) to a corresponding amino acid, forming a reactive aminoacyl adenylate intermediate and releasing inorganic pyrophosphate (PPi). Subsequently, aminoacyl tRNA synthetase binds the AMP-amino acid to a tRNA molecule, releasing AMP and attaching the amino acid to the tRNA. The resulting aminoacyl-tRNA is said to be charged.
GCN2 is a serine/threonine-protein kinase that senses amino acid deficiency through binding to uncharged transfer RNA (tRNA). It plays a key role in modulating amino acid metabolism as a response to nutrient deprivation.
Febrifugine is a quinazolinone alkaloid first isolated from the Chinese herb Dichroa febrifuga, but also found in the garden plant Hydrangea. Laboratory synthesis of febrifugine determined that the originally reported stereochemistry was incorrect.
Amino acid response is the mechanism triggered in mammalian cells by amino acid starvation.
In molecular biology, the protein domain WHEP-TRS refers to helix-turn-helix domains. They are found in variable numbers in glutamyl-prolyl tRNA synthetase (EPRS). This protein domain has an important function in protein–protein interactions between synthetases. WHEP domains exhibit high-affinity interactions with tRNA, indicating a putative evolutionary relationship to facilitate tRNA binding to fused synthetases, thereby enhancing catalytic efficiency.