Adenylate kinase functions

Mitochondria are surrounded by a simple outer membrane and a more complex inner membrane (Figure 21.1). The space between the inner and outer membranes is referred to as the intermembrane space. Several enzymes that utilize ATP (such as creatine kinase and adenylate kinase) are found in the intermembrane space. The smooth outer membrane is about 30 to 40% lipid and 60 to 70% protein, and has a relatively high concentration of phos-phatidylinositol. The outer membrane contains significant amounts of porin —a transmembrane protein, rich in /3-sheets, that forms large channels across the membrane, permitting free diffusion of molecules with molecular weights of about 10,000 or less. Apparently, the outer membrane functions mainly to... 

Mazzotta, M.Y. Johnson, E.J. Adenylate kinase from Thiobacillus neapoli-tanus. Unique properties, possibly designed to serve a unique metabolic function. Biochim. Biophys. Acta, 321, 512-525 (1973)... 

Sheng, X. Pan, X. Wang, C. Zhang, Y. Jing, G. Conformational and functional significance of residue proline 17 in chicken muscle adenylate kinase. FEBS Lett., 508, 318-322 (2001)... 

Stolworthy, T.S. Black, M.E. The mouse guanylate kinase double mutant E72Q/D103N is a functional adenylate kinase. Protein Eng., 14, 903-909 (2001)... 

Nucleoside diphosphates (NDP) are synthesized from the corresponding nucleoside monophosphates (NMP) by base-specific nucleoside monophosphate kinases (Figure 22.9). [Note These kinases do not discriminate between ribose or deoxyribose in the substrate.] ATP is generally the source of the transferred phosphate, because it is present in higher concentrations than the other nucleoside triphosphates. Adenylate kinase is particularly active in liver and muscle, where the turnover of energy from ATP is high. Its function is to maintain an equilibrium among AMP, ADP, and ATP. Nucleoside diphosphates and triphosphates are interconverted by nucleoside diphosphate kinase—an enzyme that, unlike the monophosphate kinases, has broad specificity. 

Adenylate kinase performs the essential function of recovering AMP formed by many enzymatic processes and converting it to ADP (Eq. 6-65) which can be reconverted to ATP by oxidative or substrate level phosphorylation. The enzyme is present in all organisms. In vertebrates different isoenzymes function in the cytosol, mitochondrial intermembrane space, and mitochondrial matrix.862 863 A group of other nucleotide and deoxynucleotide kinases convert nucleoside monophosphates into diphosphates.864 865 Some of them, e.g., uridylate kinase are similar in structure and properties to adenylate kinase.866 867 Another member of the adenylate kinase family is phosphoribulokinase, an important photosynthetic enzyme (see Fig. 17-14, step a).868... 

Adenylate kinase 303, 654, 655s fold 658, 659 functions of 655 Adenylate system 302-304 storage of energy 302 5 -Adenylic acid. See AMP Adenylosuccinate lyase 685 Adenylylation 545... 

Relative concentrations of ATP, ADP, and AMP as a function of the adenylate energy charge. The adenylate kinase reaction was assumed to be at equilibrium, and a value of 1.2 was used for its effective equilibrium constant in the direction shown in the equation in the text. 

According to the conventional model, anti-apoptotic Bcl-2 proteins inhibit apoptosis by functional suppression of pro-apoptotic Bcl-2 family proteins the latter promote the release of proteins (e.g. cytochrome c, apoptosis-inducing factor (AIF), adenylate kinase-2, HSP60) from the mitochondrial membrane which induce cell death by apoptosis through interactions with Apaf-1 and downstream execution enzymes50,66,69,137. A rheostat mechanism has been proposed, in which the balance of expression between pro- and anti-apoptotic Bcl-2 family members ultimately dictates the life or death decisions of a given cell4. 

Adenylate kinase, which is abundant in muscle as in many other tissues, decreases in dystrophic mouse and human muscle (H6, P7). This enzyme, by interconverting adenine nucleotides, probably functions in the control of glycolysis it seems reasonable to suppose, therefore, that its activity may be governed by the same factors which influence glycolytic enzymes, as discussed above. A severe decline in the activity of AMP deaminase occurs in muscular dystrophy (P6, P7) and also in denervated muscle (M12) and in some cases of muscle affected by hypokalemic periodic paralysis (E6). Skeletal muscle normally contains a higher concentration of this enzyme than other tissues in fact, it is almost absent from some, such as liver. Its physiological function, and hence the significance of the sharp decline in its activity in diseased muscle, is still a matter of speculation. 

Fig. 14. Stereo views of various structures related to dehydrogenases by having similar nucleotide binding function and/or similar structures. Views are oriented as in Fig. 2 for the dehydrogenases, showing (a) flavodoxin, (b) adenylate kinase, (c) the ADP binding lobe of phosphoglycerate kinase, and (d) the central portion of subtilisin.

A major function of the Bcl-2 family members is to regulate cytochrome c release via their interaction with the outer mitochondrial membrane. As described above, cytochrome c release is an important first step in initiating apoptotic events in cells because of its ability to interact with and thereby activate Apaf-1. However, mitochondria can also release a number of other proteins during apoptosis, such as AIF, certain procaspases, catabolic enzymes, adenylate kinase 2 and SMAC/Diablo. The role of these proteins in the apoptotic process is not known with certainty. Anti-apoptotic proteins of the Bcl-2 family possess membrane anchoring domains at their carboxy terminus that target the... 

Through the medium of this proticity, the cell accomplishes mechanical, osmotic, thermal, and electrical work. In this view, the central role of ATP and similar compounds in these functions is related not merely to their possession of high-energy bonds, but to their stability in the aqueous phase, which allows them to act as reservoirs which can provide proton current on demand. The presence of equilibrating mechanisms such as the adenylate kinase system ensures that local ATP depletion at any point in the cell is rapidly buffered. 

To summarize, all the above studies clearly indicate the existence of multiple timescales in the hydration-layer dynamics. While a large fraction of hydration-layer water remains almost as fast as its bulk counterpart, a sizable fraction is slow. It is conceivable that the slow water molecules reside near the hydrophilic residues that provide stability to the enzymes, while the fast water molecules participate in the biological activities. For example, in adenylate kinase catalysis, one finds that water molecules play an important functional role, which has been discussed earlier in Chapter 7, section 7.2. 

Fig. 1. Unfolding isothenn of the trimeric adenylate kinase from Sulfolobus acidocaldarius using CD spectroscopy. The squares represent the measured CD values at 222 nm versus the corresponding guanidinium chloride concentration at 40°. A linear dependence outside the transition region is assumed. The linear extrapolations of the pre- and posttransitional parts of the isotherms (solid lines) and the corresponding expressions are shown. The dotted line represents a fit using a function from Backmann et of for a trimeric protein.

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