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Article ; Online: Unraveling the folding and dimerization properties of the human FoxP subfamily of transcription factors

Villalobos, Pablo / Carvajal, Alonso I. / Castro‐Fernández, Víctor / Babul, Jorge / Ramírez‐Sarmiento, César A. / Medina, Exequiel

FEBS Letters. 2023 July, v. 597, no. 14 p.1894-1905

2023

Abstract: Human FoxP proteins share a highly conserved DNA‐binding domain that dimerizes via three‐dimensional domain swapping, although showing varying oligomerization propensities among its members. Here, we present an experimental and computational ... ...

Abstract	Human FoxP proteins share a highly conserved DNA‐binding domain that dimerizes via three‐dimensional domain swapping, although showing varying oligomerization propensities among its members. Here, we present an experimental and computational characterization of all human FoxP proteins to unravel how their amino acid substitutions impact their folding and dimerization mechanism. We solved the crystal structure of the forkhead domain of FoxP4 to then perform a comparison across all members, finding that their sequence changes impact not only the structural heterogeneity of their forkhead domains but also the protein–protein association energy barrier. Lastly, we demonstrate that the accumulation of a monomeric intermediate is an oligomerization‐dependent feature rather than a common aspect of monomers and dimers in this protein subfamily.
Keywords	DNA-binding domains ; amino acids ; crystal structure ; dimerization ; energy ; humans ; oligomerization
Language	English
Dates of publication	2023-07
Size	p. 1894-1905.
Publishing place	John Wiley & Sons, Ltd
Document type	Article ; Online
Note	JOURNAL ARTICLE
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1002/1873-3468.14665
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Article ; Online: Structure of an ancestral ADP-dependent kinase with fructose-6P reveals key residues for binding, catalysis, and ligand-induced conformational changes.

Muñoz, Sebastián M / Castro-Fernandez, Victor / Guixé, Victoria

The Journal of biological chemistry

2020 Volume 296, Page(s) 100219

Abstract: ADP-dependent kinases were first described in archaea, although their presence has also been reported in bacteria and eukaryotes (human and mouse). This enzyme family comprises three substrate specificities; specific phosphofructokinases (ADP-PFKs), ... ...

Abstract	ADP-dependent kinases were first described in archaea, although their presence has also been reported in bacteria and eukaryotes (human and mouse). This enzyme family comprises three substrate specificities; specific phosphofructokinases (ADP-PFKs), specific glucokinases (ADP-GKs), and bifunctional enzymes (ADP-PFK/GK). Although many structures are available for members of this family, none exhibits fructose-6-phosphate (F6P) at the active site. Using an ancestral enzyme, we obtain the first structure of an ADP-dependent kinase (AncMsPFK) with F6P at its active site. Key residues for sugar binding and catalysis were identified by alanine scanning, D36 being a critical residue for F6P binding and catalysis. However, this residue hinders glucose binding because its mutation to alanine converts the AncMsPFK enzyme into a specific ADP-GK. Residue K179 is critical for F6P binding, while residues N181 and R212 are also important for this sugar binding, but to a lesser extent. This structure also provides evidence for the requirement of both substrates (sugar and nucleotide) to accomplish the conformational change leading to a closed conformation. This suggests that AncMsPFK mainly populates two states (open and closed) during the catalytic cycle, as reported for specific ADP-PFK. This situation differs from that described for specific ADP-GK enzymes, where each substrate independently causes a sequential domain closure, resulting in three conformational states (open, semiclosed, and closed).
MeSH term(s)	Amino Acid Sequence ; Archaeal Proteins/chemistry ; Archaeal Proteins/genetics ; Archaeal Proteins/metabolism ; Binding Sites ; Biocatalysis ; Cloning, Molecular ; Crystallography, X-Ray ; Escherichia coli/genetics ; Escherichia coli/metabolism ; Fructosephosphates/chemistry ; Fructosephosphates/metabolism ; Gene Expression ; Genetic Vectors/chemistry ; Genetic Vectors/metabolism ; Glucokinase/chemistry ; Glucokinase/genetics ; Glucokinase/metabolism ; Kinetics ; Ligands ; Methanosarcinales/chemistry ; Methanosarcinales/enzymology ; Methanosarcinales/genetics ; Models, Molecular ; Phosphofructokinases/chemistry ; Phosphofructokinases/genetics ; Phosphofructokinases/metabolism ; Phosphotransferases (Alcohol Group Acceptor)/chemistry ; Phosphotransferases (Alcohol Group Acceptor)/genetics ; Phosphotransferases (Alcohol Group Acceptor)/metabolism ; Protein Binding ; Protein Conformation, alpha-Helical ; Protein Conformation, beta-Strand ; Protein Interaction Domains and Motifs ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Sequence Alignment ; Sequence Homology, Amino Acid ; Substrate Specificity
Chemical Substances	Archaeal Proteins ; Fructosephosphates ; Ligands ; Recombinant Proteins ; fructose-6-phosphate (6814-87-5) ; Phosphofructokinases (EC 2.7.1 -) ; Phosphotransferases (Alcohol Group Acceptor) (EC 2.7.1.-) ; ADP D-fructose-6-phosphate 1-phosphotransferase (EC 2.7.1.146) ; Glucokinase (EC 2.7.1.2)
Language	English
Publishing date	2020-12-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.RA120.015376
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Article ; Online: Characterisation of kinetics, substrate inhibition and product activation by AMP of bifunctional ADP-dependent glucokinase/phosphofructokinase from Methanococcus maripaludis.

Vallejos-Baccelliere, Gabriel / Kaufman, Sergio B / González-Lebrero, Rodolfo M / Castro-Fernandez, Víctor / Guixé, Victoria

The FEBS journal

2022 Volume 289, Issue 23, Page(s) 7519–7536

Abstract: Methanogenic archaea have received attention due to their potential use in biotechnological applications such as methane production, so their metabolism and regulation are topics of special interest. When growing in a nutrient-rich medium, these ... ...

Abstract	Methanogenic archaea have received attention due to their potential use in biotechnological applications such as methane production, so their metabolism and regulation are topics of special interest. When growing in a nutrient-rich medium, these organisms exhibit gluconeogenic metabolism; however, under starvation conditions, they turn to glycolytic metabolism. To date, no regulatory mechanism has been described for this gluconeogenic/glycolytic metabolic switch. Here, we report that adenosine monophosphate (AMP) activates both enzymatic activities of the bifunctional adenosine diphosphate (ADP)-dependent phosphofructokinase/glucokinase from Methanococcus maripaludis (MmPFK/GK). To understand this phenomenon, we performed a comprehensive kinetic characterisation, including determination of the kinetics, substrate inhibition and AMP activation mechanism of this enzyme. We determined that MmPFK/GK has an ordered-sequential mechanism, in which MgADP is the first substrate to bind and AMP is the last product released. The enzyme also displays substrate inhibition by both sugar substrates; we determined that this inhibition occurs through the formation of catalytically nonproductive enzyme complexes caused by sugar binding. For both activities, the AMP activation mechanism occurs primarily through incremental changes in the affinity for the sugar substrate, with this effect being higher in the GK than in the PFK activity. Interestingly, due to the increase in the sugar substrate affinity caused by AMP, an enhancement in the sugar substrate inhibition effect was also observed for both activities, which can be explained by an increase in sugar binding leading to the formation of dead-end complexes. These results shed light on the regulatory mechanisms of methanogenic archaeal sugar metabolism, a phenomenon that has been largely unexplored.
MeSH term(s)	Phosphofructokinases ; Adenosine Diphosphate ; Adenosine Monophosphate ; Methanococcus/genetics ; Sugars
Chemical Substances	Phosphofructokinases (EC 2.7.1 -) ; Adenosine Diphosphate (61D2G4IYVH) ; Adenosine Monophosphate (415SHH325A) ; ADP-dependent glucokinase (EC 2.7.1.-) ; Sugars
Language	English
Publishing date	2022-06-29
Publishing country	England
Document type	Journal Article
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.16557
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Article ; Online: Unraveling the folding and dimerization properties of the human FoxP subfamily of transcription factors.

Villalobos, Pablo / Carvajal, Alonso I / Castro-Fernández, Víctor / Babul, Jorge / Ramírez-Sarmiento, César A / Medina, Exequiel

FEBS letters

2023 Volume 597, Issue 14, Page(s) 1894–1905

Abstract: Human FoxP proteins share a highly conserved DNA-binding domain that dimerizes via three-dimensional domain swapping, although showing varying oligomerization propensities among its members. Here, we present an experimental and computational ... ...

Abstract	Human FoxP proteins share a highly conserved DNA-binding domain that dimerizes via three-dimensional domain swapping, although showing varying oligomerization propensities among its members. Here, we present an experimental and computational characterization of all human FoxP proteins to unravel how their amino acid substitutions impact their folding and dimerization mechanism. We solved the crystal structure of the forkhead domain of FoxP4 to then perform a comparison across all members, finding that their sequence changes impact not only the structural heterogeneity of their forkhead domains but also the protein-protein association energy barrier. Lastly, we demonstrate that the accumulation of a monomeric intermediate is an oligomerization-dependent feature rather than a common aspect of monomers and dimers in this protein subfamily.
MeSH term(s)	Humans ; Dimerization ; Transcription Factors/metabolism ; Amino Acid Sequence ; Repressor Proteins/metabolism ; Protein Domains ; Forkhead Transcription Factors/metabolism ; Protein Folding
Chemical Substances	Transcription Factors ; Repressor Proteins ; Forkhead Transcription Factors
Language	English
Publishing date	2023-05-25
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1002/1873-3468.14665
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Article ; Online: Characterisation of kinetics, substrate inhibition and product activation by AMP of bifunctional ADP‐dependent glucokinase/phosphofructokinase from Methanococcus maripaludis

Vallejos‐Baccelliere, Gabriel / Kaufman, Sergio B. / González‐Lebrero, Rodolfo M. / Castro‐Fernandez, Víctor / Guixé, Victoria

The FEBS Journal. 2022 Dec., v. 289, no. 23 p.7519-7536

2022

Abstract	Methanogenic archaea have received attention due to their potential use in biotechnological applications such as methane production, so their metabolism and regulation are topics of special interest. When growing in a nutrient‐rich medium, these organisms exhibit gluconeogenic metabolism; however, under starvation conditions, they turn to glycolytic metabolism. To date, no regulatory mechanism has been described for this gluconeogenic/glycolytic metabolic switch. Here, we report that adenosine monophosphate (AMP) activates both enzymatic activities of the bifunctional adenosine diphosphate (ADP)‐dependent phosphofructokinase/glucokinase from Methanococcus maripaludis (MmPFK/GK). To understand this phenomenon, we performed a comprehensive kinetic characterisation, including determination of the kinetics, substrate inhibition and AMP activation mechanism of this enzyme. We determined that MmPFK/GK has an ordered‐sequential mechanism, in which MgADP is the first substrate to bind and AMP is the last product released. The enzyme also displays substrate inhibition by both sugar substrates; we determined that this inhibition occurs through the formation of catalytically nonproductive enzyme complexes caused by sugar binding. For both activities, the AMP activation mechanism occurs primarily through incremental changes in the affinity for the sugar substrate, with this effect being higher in the GK than in the PFK activity. Interestingly, due to the increase in the sugar substrate affinity caused by AMP, an enhancement in the sugar substrate inhibition effect was also observed for both activities, which can be explained by an increase in sugar binding leading to the formation of dead‐end complexes. These results shed light on the regulatory mechanisms of methanogenic archaeal sugar metabolism, a phenomenon that has been largely unexplored.
Keywords	Methanococcus maripaludis ; adenosine diphosphate ; adenosine monophosphate ; glucokinase ; glycolysis ; methane production ; methanogens ; phosphofructokinases ; starvation ; sugars
Language	English
Dates of publication	2022-12
Size	p. 7519-7536.
Publishing place	John Wiley & Sons, Ltd
Document type	Article ; Online
Note	JOURNAL ARTICLE
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.16557
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Article ; Online: Kinetic characterization and phylogenetic analysis of human ADP-dependent glucokinase reveal new insights into its regulatory properties

Herrera-Morandé, Alejandra / Vallejos-Baccelliere, Gabriel / Cea, Pablo A. / Zamora, Ricardo A. / Cid, Dixon / Maturana, Pablo / González-Ordenes, Felipe / Castro-Fernández, Víctor / Guixé, Victoria

Archives of Biochemistry and Biophysics. 2023 Apr. 19, p.109602-

2023 , Page(s) 109602–

Abstract: Although ADP-dependent sugar kinases were first described in archaea, at present, the presence of an ADP-dependent glucokinase (ADP-GK) in mammals is well documented. This enzyme is mainly expressed in hematopoietic lineages and tumor tissues, although ... ...

Abstract	Although ADP-dependent sugar kinases were first described in archaea, at present, the presence of an ADP-dependent glucokinase (ADP-GK) in mammals is well documented. This enzyme is mainly expressed in hematopoietic lineages and tumor tissues, although its role has remained elusive. Here, we report a detailed kinetic characterization of the human ADP-dependent glucokinase (hADP-GK), addressing the influence of a putative signal peptide for endoplasmic reticulum (ER) destination by characterizing a truncated form. The truncated form revealed no significant impact on the kinetic parameters, showing only a slight increase in the Vmax value, higher metal promiscuity, and the same nucleotide specificity as the full-length enzyme. hADP-GK presents an ordered sequential kinetic mechanism in which MgADP is the first substrate to bind and AMP is the last product released, being the same mechanism described for archaeal ADP-dependent sugar kinases, in agreement with the protein topology. Substrate inhibition by glucose was observed due to sugar binding to nonproductive species. Although Mg²⁺ is an essential component for kinase activity, it also behaves as a partial mixed-type inhibitor for hADP-GK, mainly by decreasing the MgADP affinity. Regarding its distribution, phylogenetic analysis shows that ADP-GK´s are present in a wide diversity of eukaryotic organisms although it is not ubiquitous. Eukaryotic ADP-GKs sequences cluster into two main groups, showing differences in the highly conserved sugar-binding motif reported for archaeal enzymes [NX(N)XD] where a cysteine residue is found instead of asparagine in a significant number of enzymes. Site directed mutagenesis of the cysteine residue by asparagine produces a 6-fold decrease in Vₘₐₓ, suggesting a role for this residue in the catalytic process, probably by facilitating the proper orientation of the substrate to be phosphorylated.
Keywords	Archaea ; asparagine ; biophysics ; catalytic activity ; cysteine ; endoplasmic reticulum ; glucokinase ; glucose ; humans ; mutagenesis ; neoplasms ; phylogeny ; signal peptide ; topology ; Human ADP-Dependent glucokinase ; Ribokinase superfamily ; Mg2+ regulation ; Kinetic mechanism ; Inhibitory mechanism ; Phylogenetic analyses ; ADP ; ADP-GK ; AMP ; ATP ; G6P ; GK ; Glc ; hADP-GK ; NAD+ ; NADH ; PFK
Language	English
Dates of publication	2023-0419
Publishing place	Elsevier Inc.
Document type	Article ; Online
Note	Pre-press version
ZDB-ID	523-x
ISSN	1096-0384 ; 0003-9861
ISSN (online)	1096-0384
ISSN	0003-9861
DOI	10.1016/j.abb.2023.109602
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Article ; Online: Metal Ions Can Modulate the Self-Assembly and Activity of Catalytic Peptide Amyloids.

Duran-Meza, Eva / Araya-Secchi, Raul / Romero-Hasler, Patricio / Soto-Bustamante, Eduardo Arturo / Castro-Fernandez, Victor / Castillo-Caceres, Claudio / Monasterio, Octavio / Diaz-Espinoza, Rodrigo

Langmuir : the ACS journal of surfaces and colloids

2024 Volume 40, Issue 12, Page(s) 6094–6106

Abstract: Rational design of peptides has become a powerful tool to produce self-assembled nanostructures with the ability to catalyze different chemical reactions, paving the way to develop minimalistic enzyme-like nanomaterials. Catalytic amyloid-like assemblies ...

Abstract	Rational design of peptides has become a powerful tool to produce self-assembled nanostructures with the ability to catalyze different chemical reactions, paving the way to develop minimalistic enzyme-like nanomaterials. Catalytic amyloid-like assemblies have emerged among the most versatile and active, but they often require additional factors for activity. Elucidating how these factors influence the structure and activity is key for the design. Here, we showed that biologically relevant metal ions can guide and modulate the self-assembly of a small peptide into diverse amyloid architectures. The morphology and catalytic activity of the resulting fibrils were tuned by the specific metal ion decorating the surface, whereas X-ray structural analysis of the amyloids showed ion-dependent shape sizes. Molecular dynamics simulations showed that the metals can strongly affect the local conformational space, which can trigger major rearrangements of the fibrils. Our results demonstrate that the conformational landscape of catalytic amyloids is broad and tunable by external factors, which can be critical for future design strategies.
MeSH term(s)	Amyloid/chemistry ; Peptides/chemistry ; Metals/chemistry ; Amyloidogenic Proteins ; Ions
Chemical Substances	Amyloid ; Peptides ; Metals ; Amyloidogenic Proteins ; Ions
Language	English
Publishing date	2024-03-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	2005937-1
ISSN	1520-5827 ; 0743-7463
ISSN (online)	1520-5827
ISSN	0743-7463
DOI	10.1021/acs.langmuir.3c02983
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Article ; Online: Structural insights into a functional unit from an immunogenic mollusk hemocyanin.

Muñoz, Sebastián M / Vallejos-Baccelliere, Gabriel / Manubens, Augusto / Salazar, Michelle L / Nascimento, Andrey F Z / Tapia-Reyes, Patricio / Meneses, Claudio / Ambrosio, Andre L B / Becker, María Inés / Guixé, Victoria / Castro-Fernandez, Victor

Structure (London, England : 1993)

2024

Abstract: Mollusk hemocyanins, among the largest known proteins, are used as immunostimulants in biomedical and clinical applications. The hemocyanin of the Chilean gastropod Concholepas concholepas (CCH) exhibits unique properties, which makes it safe and ... ...

Abstract	Mollusk hemocyanins, among the largest known proteins, are used as immunostimulants in biomedical and clinical applications. The hemocyanin of the Chilean gastropod Concholepas concholepas (CCH) exhibits unique properties, which makes it safe and effective for human immunotherapy, as observed in animal models of bladder cancer and melanoma, and dendritical cell vaccine trials. Despite its potential, the structure and amino acid sequence of CCH remain unknown. This study reports two sequence fragments of CCH, representing three complete functional units (FUs). We also determined the high-resolution (1.5 Å) X-ray crystal structure of an "FU-g type" from the CCHB subunit. This structure enables in-depth analysis of chemical interactions at the copper-binding center and unveils an unusual, truncated N-glycosylation pattern. These features are linked to eliciting more robust immunological responses in animals, offering insights into CCH's enhanced immunostimulatory properties and opening new avenues for its potential applications in biomedical research and therapies.
Language	English
Publishing date	2024-03-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	1213087-4
ISSN	1878-4186 ; 0969-2126
ISSN (online)	1878-4186
ISSN	0969-2126
DOI	10.1016/j.str.2024.02.018
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Article: Structural and Kinetic Insights Into the Molecular Basis of Salt Tolerance of the Short-Chain Glucose-6-Phosphate Dehydrogenase From

Fuentes-Ugarte, Nicolás / Herrera, Sixto M / Maturana, Pablo / Castro-Fernandez, Victor / Guixé, Victoria

Frontiers in microbiology

2021 Volume 12, Page(s) 730429

Abstract: Halophilic enzymes need high salt concentrations for activity and stability and are considered a promising source for biotechnological applications. The model study for haloadaptation has been proteins from ... ...

Abstract	Halophilic enzymes need high salt concentrations for activity and stability and are considered a promising source for biotechnological applications. The model study for haloadaptation has been proteins from the
Language	English
Publishing date	2021-09-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587354-4
ISSN	1664-302X
ISSN	1664-302X
DOI	10.3389/fmicb.2021.730429
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Article ; Online: Kinetic characterization and phylogenetic analysis of human ADP-dependent glucokinase reveal new insights into its regulatory properties.

Herrera-Morandé, Alejandra / Vallejos-Baccelliere, Gabriel / Cea, Pablo A / Zamora, Ricardo A / Cid, Dixon / Maturana, Pablo / González-Ordenes, Felipe / Castro-Fernández, Víctor / Guixé, Victoria

Archives of biochemistry and biophysics

2023 Volume 741, Page(s) 109602

Abstract	Although ADP-dependent sugar kinases were first described in archaea, at present, the presence of an ADP-dependent glucokinase (ADP-GK) in mammals is well documented. This enzyme is mainly expressed in hematopoietic lineages and tumor tissues, although its role has remained elusive. Here, we report a detailed kinetic characterization of the human ADP-dependent glucokinase (hADP-GK), addressing the influence of a putative signal peptide for endoplasmic reticulum (ER) destination by characterizing a truncated form. The truncated form revealed no significant impact on the kinetic parameters, showing only a slight increase in the Vmax value, higher metal promiscuity, and the same nucleotide specificity as the full-length enzyme. hADP-GK presents an ordered sequential kinetic mechanism in which MgADP is the first substrate to bind and AMP is the last product released, being the same mechanism described for archaeal ADP-dependent sugar kinases, in agreement with the protein topology. Substrate inhibition by glucose was observed due to sugar binding to nonproductive species. Although Mg
MeSH term(s)	Humans ; Adenosine Diphosphate/metabolism ; Amino Acid Sequence ; Asparagine ; Cysteine ; Glucokinase/chemistry ; Glucose/metabolism ; Kinetics ; Phylogeny ; Sugars
Chemical Substances	Adenosine Diphosphate (61D2G4IYVH) ; ADP-dependent glucokinase (EC 2.7.1.-) ; Asparagine (7006-34-0) ; Cysteine (K848JZ4886) ; Glucokinase (EC 2.7.1.2) ; Glucose (IY9XDZ35W2) ; Sugars
Language	English
Publishing date	2023-04-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	523-x
ISSN	1096-0384 ; 0003-9861
ISSN (online)	1096-0384
ISSN	0003-9861
DOI	10.1016/j.abb.2023.109602
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