Адам ағзасындағы тафаззин протеині

Protein found in humans
Tafazzin is a protein that in humans is encoded by the TAFAZZIN gene. Tafazzin is highly expressed in cardiac and skeletal muscle, and functions as a phospholipid lysophospholipid transacylase (it belongs to phospholipid:diacylglycerol acyltransferases). It catalyzes remodeling of immature cardiolipin to its mature composition containing a predominance of tetralinoleoyl moieties. Several different isoforms of the tafazzin protein are produced from the TAFAZZIN gene. A long form and a short form of each of these isoforms is produced; the short form lacks a hydrophobic leader sequence and may exist as a cytoplasmic protein rather than being membrane bound. Other alternatively spliced transcripts have been described but the full length nature of all these transcripts is not known. Most isoforms are found in all tissues, but some are found only in certain types of cells. It is important to note that the TAZ gene was frequently confused with a protein called TAZ (transcriptional coactivator with PDZ binding motif, a 50 kDA protein). which is a part of the Hippo pathway and entirely unrelated to the gene of interest. The Hippo pathway TAZ protein has an official gene symbol of WWTR1.

The TAFAZZIN gene is located on the q arm of chromosome X at position 28 and it spans 10,208 base pairs. The structure of the encoded protein has been found to differ at their N terminus and the central region, which are two functionally notable regions. A 30 residue hydrophobic stretch at the N terminus may function as a membrane anchor, which does not exist in the shortest forms of tafazzins. The second region is a variable exposed loop located between amino acids 124 and 195 in the central region. This hydrophilic region is known to interact with other proteins. TAZ has no known resemblance to other proteins. The half life of tafazzin is just 3–6 hours, considerably shorter than most mitochondrial proteins, which may explain research difficulties in studying its structure. The putative phospholipid binding site, which is the active site of Tafazzin, is a 57 amino acid cleft with two open ends and positively charged residues. In addition, tafazzin localizes to the membrane leaflets facing the intermembrane space (IMS), which is crucial for remodeling. Tafazzin differs from phospholipases in that it contains a conserved histidine residue, His 77, as part of the conserved HX4D motif seen in acyltransferases. This motif is responsible for facilitating the Asp His dyad mechanism seen in many serine proteases. Many unique forms of tafazzin have been identified, with lengths from 129 to 292 amino acids. The TAFAZZIN gene contains two peptides independent of its active site for directing the protein to the mitochondria, forming residues 84–95 in exon 3 and residues 185–200 in exon 7/8 targets. Tafazzin localizes with peripheral association to membrane leaflets between the inner mitochondrial membrane (IMM) and outer mitochondrial membrane (OMM), facing the intermembrane space (IMS). Finally, the translocase of the outer membrane (TOM) and the translocase of the inner membrane (TIM) mediates tafazzin's movement and insertion into the OMM and anchoring to IMM.

After its synthesis, cardiolipin cannot exert its proper functions until it is actively remodeled. Tafazzin, an acyl specific transferase, catalyzes the acyl transfer reaction between phospholipids and lysophospholipids in a CoA independent manner. The remodeling process of cardiolipin involves reaching a final acyl composition that is primarily linoleoyl residues. TAZ interacts with an immature cardiolipin by adding the fatty acid linoleic acid, which catalyzes the remodeling of the cardiolipin. The remodeling is achieved by transacylation or the deacylation reacylation cycle. The deacylation reacylation cycle, also known as the Lands cycle, begins with deacylation mediated by phospholipase Cld1 to form monolysocardiolipin (MLCL). MLCL is reacylated by tafazzin in a single step reaction which transfers a linoleic acid group from phosphatidylcholine (PC), completing the CL deacylation reacylation cycle. In contrast, transacylation involves the transfer of a linoleic acid group from phosphatidylcholine (PC) to MLCL. Such enzymatic activity forms lyso PC and CL, and enriches the specific acyl chain of cardiolipin. The process has been shown to be specific for linoleoyl containing PC. Such remodeling processes converts cardiolipin into a mature composition that contains a predominance of tetralinoleoyl moieties. CL remodeling in mammals requires additional enzymes, such as monolysocardiolipin acyltransferase (MLCLAT), acyl CoA:lysocardiolipin acyltransferase (ALCAT), and phospholipase. The process enables the proper function of cardiolipin.

Tafazzin in CL remodeling has been shown to have a clear preference for linoleoyl containing PC in forming mature CL. This specificity leads a mature composition of CL that contains a predominance of tetralinoleoyl moieties, which leads to the enrichment of tetralinoleoyl cardiolipin (CL4). or the inherent enzymatic preference of tafazzin for specific acyl residues. maintaining respiratory chain supercomplex formation with proteins localized in the inner mitochondrial matrix including ATP/ADP translocase, pyruvate carrier, carnitine carrier, and all of the respiratory chain complexes (I, III, IV, V). During apoptosis and similar processes, CL is known to act as a platform for proteins and other machinery involved with its interactions with members of the Bcl 2 family, caspases, Bid, Bax, and Bak.

Mutations in the TAFAZZIN gene have been associated with a number of mitochondrial deficiencies and associated disorders including Barth syndrome, dilated cardiomyopathy (DCM), hypertrophic DCM, endocardial fibroelastosis, and left ventricular noncompaction (LVNC). More than 160 mutations in the TAFAZZIN gene have been linked to this disease. It is a rare disease, found in 1 out of every 300,000 to 400,000 live births, though it is widely known that the disease is underdiagnosed. Although BTHS occurs almost exclusively in males, there has been one identified case of BTHS in a female patient. Tafazzin is responsible for remodeling of a phospholipid cardiolipin (CL), the signature lipid of the mitochondrial inner membrane. TAFAZZIN gene mutations that cause Barth syndrome result in the production of tafazzin proteins with little or no function. As a result, linoleic acid is not added to cardiolipin, which disrupts normal mitochondrial shape and function, including energy production and protein transport. Barth syndrome patients exhibit defects in cardiolipin metabolism, including aberrant cardiolipin fatty acyl composition, accumulation of monolysocardiolipin (MLCL), and reduced total cardiolipin levels. This may lead to acute metabolic decompensation and sudden death. Tissues with high energy demands, such as the heart and other muscles, are most susceptible to cell death due to reduced energy production in mitochondria and protein transport. Additionally, affected white blood cells have abnormally shaped mitochondria, which could impair their ability to grow (proliferate) and mature (differentiate), leading to a weakened immune system and recurrent infections. Dysfunctional mitochondria likely lead to other signs and symptoms of Barth syndrome. Common clinical manifestations include: A patient with a frame shift mutation of c.227delC displayed symptoms of neutropenia, cardiomegaly, and other common symptoms of Barth syndrome. Another c. C153G mutation resulted in severe metabolic acidosis, cardiomegaly, and other major symptoms of Barth syndrome. There is no known cure for BTHS, and treatment of BTHS is convoluted and delayed due to the disease's varying phenotypes and its sheer complexity. Further, dietary fatty acids have been used to enhance bioenergetics and cardiac function in BTHS. However, severe manifestations of the symptoms in BTHS patients require heart transplantation. Statistics show 9 out of 73 (12%) surviving patients who have undergone cardiac transplantation at the last update. Alternatively, reactive oxygen species (ROS) has been suggested as the primary cause of cardiovascular impairments in BTHS. Cardiomyopathy in BTHS is exhibited at varying levels. A cohort study of BTHS patients showed 41.5% of all diagnosed cardiomyopathies in the range from birth to one month of age, and 95% exhibited a history of cardiomyopathy. Furthermore, there have been cases with mild or late onset cardiomyopathies, such as two infantile patients without cardiomyopathic phenotypes at the time of diagnosis. Cardiomyopathy in Barth syndrome is primarily exhibited in multiple forms, including dilated cardiomyopathy (DCM), left ventricular condition in which the heart becomes weakened and enlarged, and therefore cannot pump blood efficiently. The resulting decrease in blood flow can lead to swelling in the legs and abdomen, fluid in the lungs, and an increased risk of blood clots. INVM occurs when the lower left chamber of the heart (left ventricle) does not develop correctly. In INVM, the heart muscle is weakened and cannot pump blood efficiently, frequently causing heart failure. Additional symptoms of musculoskeletal pathology include hypotonia, delayed motor development, short stature, and facial dysmorphia in varying degrees. Furthermore, it has been shown that a downshift in weight, length, and height relative to the normal population is exhibited in BTHS patients. Treatment for developmental delays have included cornstarch supplementation as an alternative source of glucose. However, no formal assessment of the utility of carnitine and arginine supplementation has been published, and its uses have only been effective in patients with specific deficiencies. and mild learning and speech difficulties One study has shown that the brain has a distinct CL composition, with more diverse and less tetralinoleoyl dependent CL. This composition diminishes the need for CL remodeling, resulting in a less tafazzin dependent composition. Finally, the brain has a higher ROS scavenging capability, which allows the circumvention of the harmful effects of ROS.

Metabolic disorders in BTHS are exhibited in the form of 3 methylglutaconic aciduria (3 MGA), a condition characterized by increased levels of organic acids in urine, including 3‐methylglutaconic acid, 3‐methylglutaric acid, and 2‐ethyl hydracrylic acid. While 3 MGA is largely excreted in BTHS patients, some patients have been found to have normal levels of organic acids in urine. Treatment of 3 MGA and metabolic deficiencies have included riboflavin or coenzyme Q10, which have shown significant improvement in patients. An absolute neutrophil count of < 500/μL, defined as severe chronic neutropenia (SCN), is the most deleterious form.

TAFAZZIN has been found to be highly expressed in gastric cancer cells resistant to cisplatin. This resistance was identified to be due to the acquired ability of the cancer cells to undergo epithelial mesenchymal transition (EMT). The findings that TAFAZZIN is involved in inducing EMT as well as its high levels in these cancer cells may point to its involvement in gastric cancer. prostate cancer, thyroid neoplasm, and cervical cancer.