Unique structural features of the adenylate kinase hCINAP/AK6 and its multifaceted functions in carcinogenesis and tumor progression

Xu, Ruidan; Yang, Yongfeng; Zheng, Xiaofeng

doi:10.1002/1873-3468.14158

Cited by 7 publications

(8 citation statements)

References 68 publications

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“…S8B and multiple alignments in [9]. In particular, all the human adenylate kinases have glycine residues in the K+1 position except adenylate kinase 6, which has a threonine residue [289]. And it is for this kinase that both kinase and ATPase activities have been shown [290].…”

Section: Discussionmentioning

confidence: 99%

Common mechanism of activated catalysis in P-loop fold nucleoside triphosphatases -in varietate concordia

Kozlova

Shalaeva

Dibrova

2022

Preprint

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Although P-loop fold nucleoside triphosphatases (also known as Walker NTPases) are ubiquitous, their catalytic mechanism remains obscure. Based on a comparative structural analysis of 3136 Mg-NTP-containing catalytic sites, we propose a common scheme of activated catalysis for P-loop NTPases where a hydrogen bond (H-bond) between the strictly conserved, Mg-coordinating Ser/Thr of the Walker A motif ([Ser/Thr]WA) and the conserved aspartate of the Walker B motif (AspWB) plays the key role. We found that this H-bond is very short in the structures with bound transition state (TS) analogs. We suggest that the proton affinities of these two residues reverse in the TS so that the proton relocates from [Ser/Thr]WA to AspWB. The anionic [Ser/Thr]WA withdraws then a proton from the (catalytic) water molecule, and the nascent hydroxyl anion attacks gamma-phosphate. When the gamma-phosphate group breaks away, the trapped proton relays from AspWB, via [Ser/Thr]WA, to beta-phosphate and compensates for its developing negative charge.

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Section: Discussionmentioning

confidence: 99%

Common mechanism of activated catalysis in P-loop fold nucleoside triphosphatases -in varietate concordia

Kozlova

Shalaeva

Dibrova

2022

Preprint

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“…To identify possible evolutionary linkages between OdinAK and human enzymes, we interrogated human sequences in UniProt with a basic local alignment search tool (BLAST) search using OdinAK as query. The top hit was found to be nuclear human AK6 (hAK6), also known as human coilin-interacting protein ( 30 ). Although hAK6 is the closest human homolog to OdinAK, the sequence similarity is limited to 19 identical residues in a 36–amino acid segment that is equivalent to the conserved Walker-A p-loop segment (fig.…”

Section: Resultsmentioning

confidence: 99%

“…8 (A and B). A notable aspect of hAK6, as inferred from its structure (PDB ID: 1RKB) ( 30 ), is that, similar to archaeal AKs, it contains the conserved histidine in the active site (Fig. 8B).…”

Section: Resultsmentioning

confidence: 99%

“…Of these enzymes, the structures have been solved for cytosolic AK1 (PDB ID: 1Z83), mitochondrial AK2 (PDB ID: 2C9Y), mitochondrial matrix AK3 (PDB ID: 6ZJB) ( 7 ), mitochondrial AK4 (PDB ID: 2AR7), cytosolic/nuclear AK5 (PDB ID: 2BWJ), and nuclear hAK6 (PDB ID: 1RKB) ( 33 ). It should be noted that it is not clear whether hAK6 works exclusively as an AK inside human cells and that it has been suggested to have roles in gene transcription, ribosome synthesis, cellular metabolism, cell proliferation, apoptosis, DNA damage responses, and genome stability ( 30 ). In addition, the catalytic turnover for the AK reaction is very slow ( k cat is equal to 0.0063 s −1 ) for hAK6 ( 34 ), and it also displays low adenosine triphosphatase (ATPase) activity ( k cat is equal to 0.00048 s −1 ) ( 34 ).…”

Section: Resultsmentioning

confidence: 99%

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Insights into the evolution of enzymatic specificity and catalysis: From Asgard archaea to human adenylate kinases

et al. 2022

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Enzymatic catalysis is critically dependent on selectivity, active site architecture, and dynamics. To contribute insights into the interplay of these properties, we established an approach with NMR, crystallography, and MD simulations focused on the ubiquitous phosphotransferase adenylate kinase (AK) isolated from Odinarchaeota (OdinAK). Odinarchaeota belongs to the Asgard archaeal phylum that is believed to be the closest known ancestor to eukaryotes. We show that OdinAK is a hyperthermophilic trimer that, contrary to other AK family members, can use all NTPs for its phosphorylation reaction. Crystallographic structures of OdinAK-NTP complexes revealed a universal NTP-binding motif, while 19 F NMR experiments uncovered a conserved and rate-limiting dynamic signature. As a consequence of trimerization, the active site of OdinAK was found to be lacking a critical catalytic residue and is therefore considered to be “atypical.” On the basis of discovered relationships with human monomeric homologs, our findings are discussed in terms of evolution of enzymatic substrate specificity and cold adaptation.

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“…That is what independently occurred in several lineages of nucleotide monophosphate kinases; see Figure S7B and multiple alignments in [ 9 ]. In particular, a glycine residues are present in the K+1 position of human adenylate kinases except for adenylate kinase 6, which has a threonine residue [ 276 ]. It is for this kinase that both kinase and ATPase activities have been shown [ 277 ].…”

Section: Discussionmentioning

confidence: 99%

Common Mechanism of Activated Catalysis in P-loop Fold Nucleoside Triphosphatases—United in Diversity

et al. 2022

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To clarify the obscure hydrolysis mechanism of ubiquitous P-loop-fold nucleoside triphosphatases (Walker NTPases), we analysed the structures of 3136 catalytic sites with bound Mg-NTP complexes or their analogues. Our results are presented in two articles; here, in the second of them, we elucidated whether the Walker A and Walker B sequence motifs—common to all P-loop NTPases—could be directly involved in catalysis. We found that the hydrogen bonds (H-bonds) between the strictly conserved, Mg-coordinating Ser/Thr of the Walker A motif ([Ser/Thr]WA) and aspartate of the Walker B motif (AspWB) are particularly short (even as short as 2.4 ångströms) in the structures with bound transition state (TS) analogues. Given that a short H-bond implies parity in the pKa values of the H-bond partners, we suggest that, in response to the interactions of a P-loop NTPase with its cognate activating partner (which are analysed in the first article, reference, Biomolecules-1832854), a proton relocates from [Ser/Thr]WA to AspWB. The resulting anionic [Ser/Thr]WA alkoxide withdraws a proton from the catalytic water molecule, and the nascent hydroxyl attacks the gamma phosphate of NTP. When the gamma-phosphate breaks away, the trapped proton at AspWB passes by the Grotthuss relay via [Ser/Thr]WA to beta-phosphate and compensates for its developing negative charge that is thought to be responsible for the activation barrier of hydrolysis.

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Unique structural features of the adenylate kinase hCINAP/AK6 and its multifaceted functions in carcinogenesis and tumor progression

Cited by 7 publications

References 68 publications

Common mechanism of activated catalysis in P-loop fold nucleoside triphosphatases -in varietate concordia

Common mechanism of activated catalysis in P-loop fold nucleoside triphosphatases -in varietate concordia

Insights into the evolution of enzymatic specificity and catalysis: From Asgard archaea to human adenylate kinases

Common Mechanism of Activated Catalysis in P-loop Fold Nucleoside Triphosphatases—United in Diversity

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