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43-416: 538 11977 ENSG00000165240 ENSMUSG00000033792 Q04656 Q64430 NM_000052 NM_001282224 NM_001109757 NM_009726 NP_000043 NP_001269153 NP_001103227 NP_033856 ATP7A , also known as Menkes' protein ( MNK ), is a copper-transporting P-type ATPase which uses the energy arising from ATP hydrolysis to transport Cu(I) across cell membranes. The ATP7A protein

86-531: A lower affinity for ATP7A compared to Zn(II); as the Cu(I) concentration increases, a dramatic increasing affinity of Cu(I) for the protein is observed. The two cysteine (C) residues in each Cu(I)-binding site are coordinated to Cu(I) with a S-Cu(I)-S angle between 120 and 180° and a Cu-S distance of 2.16 Å. Experimental results from a homologous protein ATP7B suggests that reducing reagents are involved, and upon Cu(I) binding

129-476: Is a transmembrane protein and is expressed in the intestine and all tissues except liver. In the intestine, ATP7A regulates Cu(I) absorption in the human body by transporting Cu(I) from the small intestine into the blood. In other tissues, ATP7A shuttles between the Golgi apparatus and the cell membrane to maintain proper Cu(I) concentrations (since there is no free Cu(I) in the cell, Cu(I) ions are all tightly bound) in

172-545: Is a transmembrane protein with the N- and C-termini both oriented towards the cytosol (see picture). It is highly homologous to protein ATP7B . ATP7A contains three major functional domains: Many motifs in the ATP7A structure are conserved: Between transmembrane segments 6 and 7 is a large cytoplasmic loop, where three motifs are located: DKTG, SEHPL, and GDGXND. The six Cu(I)-binding sites at

215-451: Is a highly exergonic process. The amount of released energy depends on the conditions in a particular cell. Specifically, the energy released is dependent on concentrations of ATP, ADP and P i . As the concentrations of these molecules deviate from values at equilibrium, the value of Gibbs free energy change (Δ G ) will be increasingly different. In standard conditions (ATP, ADP and P i concentrations are equal to 1M, water concentration

258-449: Is a long-term store of glucose produced by the cells of the liver . In the liver , the synthesis of glycogen is directly correlated with blood glucose concentration. High blood glucose concentration causes an increase in intracellular levels of glucose 6-phosphate in the liver, skeletal muscle , and fat ( adipose ) tissue. Glucose 6-phosphate has role in regulating glycogen synthase . High blood glucose releases insulin , stimulating

301-469: Is almost twice as much as the energy produced under standard conditions. Phosphorylation In biochemistry , phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation , are common in biology . Protein phosphorylation often activates (or deactivates) many enzymes . Phosphorylation is essential to the processes of both anaerobic and aerobic respiration , which involve

344-463: Is equal to 55 M) the value of Δ G is between -28 and -34 kJ/mol. The range of the Δ G value exists because this reaction is dependent on the concentration of Mg cations, which stabilize the ATP molecule. The cellular environment also contributes to differences in the Δ G value since ATP hydrolysis is dependent not only on the studied cell, but also on the surrounding tissue and even the compartment within

387-482: Is greatly stabilized by multiple resonance structures , making the products (ADP and P i ) lower in energy than the reactant (ATP). The high negative charge density associated with the three adjacent phosphate units of ATP also destabilizes the molecule, making it higher in energy. Hydrolysis relieves some of these electrostatic repulsions, liberating useful energy in the process by causing conformational changes in enzyme structure. In humans, approximately 60 percent of

430-481: Is maintained by inorganic phosphate. Each molecule of glyceraldehyde 3-phosphate is phosphorylated to form 1,3-bisphosphoglycerate . This reaction is catalyzed by glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The cascade effect of phosphorylation eventually causes instability and allows enzymes to open the carbon bonds in glucose. Phosphorylation functions is an extremely vital component of glycolysis, as it helps in transport, control, and efficiency. Glycogen

473-437: Is much greater than the standard value. The nonstandard conditions of the cell actually result in a more favorable reaction. In one particular study, to determine Δ G in vivo in humans, the concentration of ATP, ADP, and P i was measured using nuclear magnetic resonance. In human muscle cells at rest, the concentration of ATP was found to be around 4 mM and the concentration of ADP was around 9 μM. Inputing these values into

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516-471: Is released by the hydrolysis of ATP. However, when the P-O bonds are broken, input of energy is required. It is the formation of new bonds and lower-energy inorganic phosphate with a release of a larger amount of energy that lowers the total energy of the system and makes it more stable. Hydrolysis of the phosphate groups in ATP is especially exergonic , because the resulting inorganic phosphate molecular ion

559-501: Is the catabolic reaction process by which chemical energy that has been stored in the high-energy phosphoanhydride bonds in adenosine triphosphate (ATP) is released after splitting these bonds, for example in muscles , by producing work in the form of mechanical energy . The product is adenosine diphosphate (ADP) and an inorganic phosphate (P i ). ADP can be further hydrolyzed to give energy, adenosine monophosphate (AMP), and another inorganic phosphate (P i ). ATP hydrolysis

602-443: Is the final link between the energy derived from food or sunlight and useful work such as muscle contraction , the establishment of electrochemical gradients across membranes, and biosynthetic processes necessary to maintain life. Anhydridic bonds are often labelled as " high-energy bonds" . P-O bonds are in fact fairly strong (~30 kJ/mol stronger than C-N bonds) and themselves not particularly easy to break. As noted below, energy

645-594: The disulfide bonding between the cysteine residues is broken as cysteine starts to bind to Cu(I), leading to a series of conformational changes at the N-terminal of the protein, and possibly activating the Cu(I)-transporting activity of other cytosolic loops. Of the six copper(I)-binding sites, two are considered enough for the function of Cu(I) transport. The reason why there are six binding sites remains not fully understood. However, some scientists have proposed that

688-462: The 1 and 3 N-atoms of the imidazole ring. Recent work demonstrates widespread human protein phosphorylation on multiple non-canonical amino acids, including motifs containing phosphorylated histidine, aspartate, glutamate, cysteine , arginine and lysine in HeLa cell extracts. However, due to the chemical lability of these phosphorylated residues, and in marked contrast to Ser, Thr and Tyr phosphorylation,

731-454: The ATP7A protein has a dual role and shuttles between two locations within the cell. The protein normally resides in a cell structure called the Golgi apparatus , which modifies and transports newly produced enzymes and other proteins. Here, ATP7A supplies Cu(I) to certain enzymes (e.g. peptidyl-α-monooxygenase , tyrosinase , and lysyl oxidase ) that are critical for the structures and functions of brain, bone, skin, hair, connective tissue, and

774-399: The N-terminal bind one Cu(I) each. This binding site is not specific for Cu(I) and can bind various transition metal ions. Cd(II), Au(III) and Hg(II) bind to the binding site more tightly than does Zn(II), whereas Mn(II) and Ni(II) have lower affinities relative to Zn(II). In the case of Cu(I), a possible cooperative-binding mechanism is observed. When the Cu(I) concentration is low, Cu(I) has

817-424: The above equations yields Δ G = -64 kJ/mol. After ischemia , when the muscle is recovering from exercise, the concentration of ATP is as low as 1 mM and the concentration of ADP is around 7 μM. Therefore, the absolute Δ G would be as high as -69 kJ/mol. By comparing the standard value of Δ G and the experimental value of Δ G , one can see that the energy released from the hydrolysis of ATP, as measured in humans,

860-429: The analysis of phosphorylated histidine (and other non-canonical amino acids) using standard biochemical and mass spectrometric approaches is much more challenging and special procedures and separation techniques are required for their preservation alongside classical Ser, Thr and Tyr phosphorylation. The prominent role of protein phosphorylation in biochemistry is illustrated by the huge body of studies published on

903-538: The blood. The phosphorylation of glucose can be enhanced by the binding of fructose 6-phosphate (F6P), and lessened by the binding fructose 1-phosphate (F1P). Fructose consumed in the diet is converted to F1P in the liver. This negates the action of F6P on glucokinase, which ultimately favors the forward reaction. The capacity of liver cells to phosphorylate fructose exceeds capacity to metabolize fructose-1-phosphate. Consuming excess fructose ultimately results in an imbalance in liver metabolism, which indirectly exhausts

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946-676: The cell and provides certain enzymes with Cu(I) (e.g. peptidyl-α-monooxygenase , tyrosinase , and lysyl oxidase ). The X-linked, inherited, lethal genetic disorder of the ATP7A gene causes Menkes disease , a copper deficiency resulting in early childhood death. The ATP7A gene is located on the long (q) arm of the X chromosome at band Xq21.1. The encoded ATP7A protein has 1,500 amino acids. At least 12 disease-causing mutations in this gene have been discovered. Mutations/additions/deletions of this gene often cause copper deficiency, which leads to progressive neurodegeneration and death in children. ATP7A

989-434: The cell membrane is negatively charged. This reaction occurs due to the enzyme hexokinase , an enzyme that helps phosphorylate many six-membered ring structures. Phosphorylation takes place in step 3, where fructose-6-phosphate is converted to fructose 1,6-bisphosphate . This reaction is catalyzed by phosphofructokinase . While phosphorylation is performed by ATPs during preparatory steps, phosphorylation during payoff phase

1032-480: The cell membrane, unable to shuttle back and forth from the Golgi. As a result of the disrupted activity of the ATP7A protein, copper is poorly distributed to cells in the body. Copper accumulates in some tissues, such as the small intestine and kidneys, while the brain and other tissues have unusually low levels. The decreased supply of copper can reduce the activity of numerous copper-containing enzymes that are necessary for

1075-505: The cell. Variability in the Δ G values is therefore to be expected. The relationship between the standard Gibbs free energy change Δ r G and chemical equilibrium is revealing. This relationship is defined by the equation Δ r G = - RT ln( K ), where K is the equilibrium constant , which is equal to the reaction quotient Q in equilibrium. The standard value of Δ G for this reaction is, as mentioned, between -28 and -34 kJ/mol; however, experimentally determined concentrations of

1118-454: The concentrations are more appropriately measured in mM, which is smaller than M by three orders of magnitude. Using these nonstandard concentrations, the calculated value of Q is much less than one. By relating Q to Δ G using the equation Δ G = Δ r G + RT ln( Q ), where Δ r G is the standard change in Gibbs free energy for the hydrolysis of ATP, it is found that the magnitude of Δ G

1161-424: The conversion of D-glucose to D-glucose-6-phosphate in the first step of glycolysis is given by: Glycolysis is an essential process of glucose degrading into two molecules of pyruvate , through various steps, with the help of different enzymes. It occurs in ten steps and proves that phosphorylation is a much required and necessary step to attain the end products. Phosphorylation initiates the reaction in step 1 of

1204-418: The energy released from the hydrolysis of ATP produces metabolic heat rather than fuel the actual reactions taking place. Due to the acid-base properties of ATP, ADP, and inorganic phosphate, the hydrolysis of ATP has the effect of lowering the pH of the reaction medium. Under certain conditions, high levels of ATP hydrolysis can contribute to lactic acidosis . Hydrolysis of the terminal phosphoanhydridic bond

1247-412: The expense of solar energy by photophosphorylation in the chloroplasts of plant cells. Phosphorylation of sugars is often the first stage in their catabolism . Phosphorylation allows cells to accumulate sugars because the phosphate group prevents the molecules from diffusing back across their transporter . Phosphorylation of glucose is a key reaction in sugar metabolism. The chemical equation for

1290-424: The extracellular side. ATP7A is important for regulating copper Cu(I) in mammals. This protein is found in most tissues, but it is not expressed in the liver. In the small intestine, the ATP7A protein helps control the absorption of Cu(I) from food. After Cu(I) ions are absorbed into enterocytes , ATP7A is required to transfer them across the basolateral membrane into the circulation. In other organs and tissues,

1333-565: The heart. This further suggests a link between intermediary metabolism and cardiac growth. Protein phosphorylation is the most abundant post-translational modification in eukaryotes. Phosphorylation can occur on serine , threonine and tyrosine side chains (in other words, on their residues) through phosphoester bond formation, on histidine , lysine and arginine through phosphoramidate bonds , and on aspartic acid and glutamic acid through mixed anhydride linkages . Recent evidence confirms widespread histidine phosphorylation at both

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1376-501: The highly conserved DKTG motif, accompanied by Cu(I) release. A subsequent dephosphorylation of the intermediate finishes the catalytic cycle. Within each cycle, ATP7A interconverts between at least two different conformations, E1 and E2. In the E1 state, Cu(I) is tightly bound to the binding sites on the cytoplasmic side; in the E2 state, the affinity of ATP7A for Cu(I) decreases and Cu(I) is released on

1419-414: The involved molecules reveal that the reaction is not at equilibrium. Given this fact, a comparison between the equilibrium constant, K , and the reaction quotient, Q , provides insight. K takes into consideration reactions taking place in standard conditions, but in the cellular environment the concentrations of the involved molecules (namely, ATP, ADP, and P i ) are far from the standard 1 M. In fact,

1462-465: The liver cell's supply of ATP. Allosteric activation by glucose 6-phosphate, which acts as an effector, stimulates glycogen synthase, and glucose 6 phosphate may inhibit the phosphorylation of glycogen synthase by cyclic AMP -stimulated protein kinase . Phosphorylation of glucose is imperative in processes within the body. For example, phosphorylating glucose is necessary for insulin-dependent mechanistic target of rapamycin pathway activity within

1505-460: The liver. The liver's crucial role in controlling blood sugar concentrations by breaking down glucose into carbon dioxide and glycogen is characterized by the negative Gibbs free energy (ΔG) value, which indicates that this is a point of regulation with. The hexokinase enzyme has a low Michaelis constant (K m ), indicating a high affinity for glucose, so this initial phosphorylation can proceed even when glucose levels at nanoscopic scale within

1548-468: The milder form of Menkes disease. Many of these mutations delete part of the gene and are predicted to produce a shortened ATP7A protein that is unable to transport Cu(I). Other mutations insert additional DNA base pairs or use the wrong base pairs, which leads to ATP7A proteins that do not function properly. The altered proteins that result from ATP7A mutations impair the absorption of copper from food, fail to supply copper to certain enzymes, or get stuck in

1591-450: The nervous system. If Cu(I) levels in the cell environment are elevated, however, ATP7A moves to the cell membrane and eliminates excess Cu(I) from the cell. The functions of ATP7A in some tissues of the human body are as follows: ATP7A has been shown to interact with ATOX1 and GLRX . Antioxidant 1 copper chaperone (ATOX1) is required to maintain Cu(I) copper homeostasis in the cell. It can bind and transport cytosolic Cu(I) to ATP7A in

1634-462: The other four sites may serve as a Cu(I) concentration detector. ATP7A belongs to a transporter family called P-type ATPases , which catalyze auto- phosphorylation of a key conserved aspartic acid (D) residue within the enzyme. The first step is ATP binding to the ATP-binding domain and Cu(I) binding to the transmembrane region. Then ATP7A is phosphorylated at the key aspartic acid (D) residue in

1677-408: The preparatory step (first half of glycolysis), and initiates step 6 of payoff phase (second phase of glycolysis). Glucose, by nature, is a small molecule with the ability to diffuse in and out of the cell. By phosphorylating glucose (adding a phosphoryl group in order to create a negatively charged phosphate group ), glucose is converted to glucose-6-phosphate, which is trapped within the cell as

1720-399: The production of adenosine triphosphate (ATP), the "high-energy" exchange medium in the cell. During aerobic respiration, ATP is synthesized in the mitochondrion by addition of a third phosphate group to adenosine diphosphate (ADP) in a process referred to as oxidative phosphorylation . ATP is also synthesized by substrate-level phosphorylation during glycolysis . ATP is synthesized at

1763-729: The structure and function of bone, skin, hair, blood vessels, and the nervous system. Copper is also critical for the propagation of prion proteins, and mice with mutations in Atp7a have a delayed onset of prion disease. A comprehensive resource of clinically annotated genetic variants in ATP7A gene has been made available confirming to the American College of Medical Genetics and Genomics guidelines for interpretation of sequence variants. A proton pump inhibitor, Omeprazole, has been shown to block ATP7A, in addition to its more established role of blocking ATP4A. ATP hydrolysis ATP hydrolysis

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1806-498: The trans-Golgi-network. Glutaredoxin-1 (GRX1) has is also essential for ATP7A function. It promotes Cu(I) binding for subsequent transport by catalyzing the reduction of disulfide bridges. It may also catalyze de- glutathionylation reaction of the C (cysteine) residues within the six Cu(I)-binding motifs GMTCXXC. Menkes disease is caused by mutations in the ATP7A gene. Researchers have identified different ATP7A mutations that cause Menkes disease and occipital horn syndrome (OHS),

1849-414: The translocation of specific glucose transporters to the cell membrane; glucose is phosphorylated to glucose 6-phosphate during transport across the membrane by ATP-D-glucose 6- phosphotransferase and non-specific hexokinase (ATP-D-hexose 6-phosphotransferase). Liver cells are freely permeable to glucose, and the initial rate of phosphorylation of glucose is the rate-limiting step in glucose metabolism by

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