Changing the substrate specificity of creatine kinase from creatine to glycocyamine: Evidence for a highly evolved active site

Jourden, Michael J.; Clarke, Callisia N.; Palmer, Allyson K.; Barth, Emily J.; Prada, Rebecca C.; Hale, Robyn N.; Fraga, Dean; Snider, Mark J.; Edmiston, Paul L.

doi:10.1016/j.bbapap.2007.10.001

Cited by 12 publications

(10 citation statements)

References 47 publications

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“…Thus, it was surprising that 18 of the 19 mutations at this position altered the CK enzyme to low activity form suggesting that the active center of CK is designed in highly organized state. This is in accord with the recent communication by Jourden et al [23], reporting the difficulty of changing the substrate specificity in rabbit CK.…”

Section: Enzymatic Properties Of Residue-96 Mutants Of Danio Cksupporting

confidence: 91%

The role of Arg-96 in Danio rerio creatine kinase in substrate recognition and active center configuration

Uda

Kuwasaki

Shima

et al. 2009

International Journal of Biological Macromolecules

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Section: Enzymatic Properties Of Residue-96 Mutants Of Danio Cksupporting

confidence: 91%

The role of Arg-96 in Danio rerio creatine kinase in substrate recognition and active center configuration

Uda

Kuwasaki

Shima

et al. 2009

International Journal of Biological Macromolecules

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“…The Asn 57 C␣ is displaced 2 Å relative to LpAK Ser 63 to enlarge the binding pocket and allow for a side chain H-bond between O␦1 and the substrate nitrogen. Differences of ϳ2 Å extend back to the start of the specificity loop (Asn 54 ) and might be stabilized by an edge-to-face (herringbone) -stacking interaction unique to LK, among Phe 55 , His 17 , and Tyr 14 . Asn 57 is the site of the CK specificity loop insertion (Table 4), and the presence of Gly 56 (Asp in AK and Gly in CK) may give the flexibility needed to adopt different configurations.…”

Section: Prediction Of the Lk Transition State Form And Substrate Spementioning

confidence: 99%

“…One set (LpAK loop 59 -64) and Urechis caupo lombricine kinase (UcLK) loop [53][54][55][56][57][58] is located in the small N-terminal ␣-helical domain and facilitates binding of the phosphagen substrate through backbone hydrogen bonds to the carboxylate of the substrate. With loop length inversely correlated to substrate size, the mechanism of the small domain specificity loop has been rationalized in terms of lock-and-key steric hindrance (15,(17)(18)(19).…”

mentioning

confidence: 99%

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The Structure of Lombricine Kinase

Bush

Kirillova

Clark

et al. 2011

Journal of Biological Chemistry

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Lombricine kinase is a member of the phosphagen kinase family and a homolog of creatine and arginine kinases, enzymes responsible for buffering cellular ATP levels. Structures of lombricine kinase from the marine worm Urechis caupo were determined by x-ray crystallography. One form was crystallized as a nucleotide complex, and the other was substrate-free. The two structures are similar to each other and more similar to the substrate-free forms of homologs than to the substrate-bound forms of the other phosphagen kinases. Active site specificity loop 309 -317, which is disordered in substrate-free structures of homologs and is known from the NMR of arginine kinase to be inherently dynamic, is resolved in both lombricine kinase structures, providing an improved basis for understanding the loop dynamics. Phosphagen kinases undergo a segmented closing on substrate binding, but the lombricine kinase ADP complex is in the open form more typical of substrate-free homologs. Through a comparison with prior complexes of intermediate structure, a correlation was revealed between the overall enzyme conformation and the substrate interactions of His 178 . Comparative modeling provides a rationale for the more relaxed specificity of these kinases, of which the natural substrates are among the largest of the phosphagen substrates.Lombricine, arginine, and creatine kinases (EC 2.7.3) are homologous phosphagen kinases that catalyze the buffering of cellular ATP levels through phosphoryl transfer to/from their respective guanidino-containing substrates. The reaction is central to short-term temporal energy buffering (1, 2) as well as in spatial shuttling of energy from production to consumption sites (3-5). A wide array of endergonic processes is driven by nucleotide hydrolysis, from motion in molecular motors, active transport, and synthetic metabolism to signal transduction. Thus, the maintenance of a constant ATP/ADP ratio, displaced far from thermodynamic equilibrium in the face of high and variable rates of ATP turnover, is crucial for cellular homeostasis (2).Different organisms use different phosphagen substrates, usually only one and each with its own specific phosphagen kinase ( Fig. 1) (2). Lombricine kinase, as well as taurocyamine kinase and glycocyamine kinase, is found exclusively in annelids and allied groups (2). Phylogenetic analyses and studies of the intron/exon organization of the genes of these phosphagen kinases unique to annelids have shown that they are more closely related to creatine kinases (with which they share 50 -60% sequence identity) than typical monomeric arginine kinases such as that from the horseshoe crab (6) (40% sequence identity). Annelids are more diverse in their choice of phosphagen, and the substrate specificities of the corresponding kinases are often lower (6).Structural work has concentrated on the presumptive ancestral arginine kinase and the vertebrate creatine kinase (7, 8), but sequence alignment suggests that subunit fold, if not quaternary structure, is conserved across the fa...

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“…The second residue (Val 325 ) is only accessible (>0.5) in the open conformation. This valine residue forms a hydrophobic specificity pocket that accommodates the methyl group distinctive of Cr (Jourden et al, 2007;Lahiri et al, 2002;Novak et al, 2004), explaining why it is not accessible in the closed state anymore. The Asp 326 residue itself was also found to have a relative surface accessibility in both the open and the closed conformation, but since it is predicted to interact with His 66 in the N-terminal flexible loop upon closure, it is not expected to associate simultaneously with binding partners to facilitate recruitment.…”

Section: Ck-b's C-terminal Flexible Loop Contains Multiple Surface Acmentioning

confidence: 97%

Submembranous recruitment of creatine kinase B supports formation of dynamic actin-based protrusions of macrophages and relies on its C-terminal flexible loop

Venter

Polling

Pluk

et al. 2015

European Journal of Cell Biology

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Changing the substrate specificity of creatine kinase from creatine to glycocyamine: Evidence for a highly evolved active site

Cited by 12 publications

References 47 publications

The role of Arg-96 in Danio rerio creatine kinase in substrate recognition and active center configuration

The role of Arg-96 in Danio rerio creatine kinase in substrate recognition and active center configuration

The Structure of Lombricine Kinase

Submembranous recruitment of creatine kinase B supports formation of dynamic actin-based protrusions of macrophages and relies on its C-terminal flexible loop

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