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Biomolecules
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New Insights into Conformational Changes in Glutamine Amidotransferases
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New Insights into Conformational Changes in Glutamine Amidotransferases

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Enzymology".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 9072

Special Issue Editor

Dr. Beatrice Golinelli-Pimpaneau

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Guest Editor
Laboratoire de Chimie des Processus Biologiques, Collège de France, 75005 Paris, France
Interests: ammonia-channeling enzymes; [Fe-S]-cluster containing enzymes; sulfuration enzymes; tRNA modification; ribozymes; X-ray crystallography; enzyme mechanisms

Special Issue Information

Dear Colleagues,

Glutamine amidotransferases represent a large class of enzymes, which are interesting to target to develop new drugs. They possess at least two domains that harbor the glutaminase site, where ammonia is released, and the synthase site where it is used to aminate a second substrate, which are linked to each other by a channel. In 2006, we reported the first structural studies of a glutamine amidotransferase that highlighted the conformational changes needed to form the ammonia channel (Mouilleron et al, J. Biol Chem, 2006). We then reasoned that such a tight cooperation between the two domains should be required for efficient catalysis by all enzymes of this family (Mouilleron and Golinelli-Pimpaneau, Cur. Op. Struct. Biol., 2007).

In the last decade, the crystal structures of novel amidotransferases have been determined, as well as new substrate/inhibitor-bound forms of several enzymes, confirming the precise crosstalk between the two catalytic sites and revealing tight regulation by allosteric ligands. Moreover, Cryo-EM characterized large oligomers, representing an additional layer of metabolic regulation, whereas molecular dynamics simulations analyzed domain motions and the details of ammonia channel formation.

This Special Issue will cover recent structural insights into the mechanism of glutamine amidotransferases by emphasizing the conformational changes occurring during catalysis, as well as allosteric regulation by small molecules.

Dr. Beatrice Golinelli-Pimpaneau
Guest Editor

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Keywords

  • ammonia channel
  • glutamine amidotransferase
  • conformational changes
  • allosteric regulation

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Published Papers (3 papers)

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Research

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15 pages, 3096 KiB  
Article
Tertiary and Quaternary Structure Organization in GMP Synthetases: Implications for Catalysis
by Lionel Ballut, Sébastien Violot, Frédéric Galisson, Isabelle R. Gonçalves, Juliette Martin, Santosh Shivakumaraswamy, Loïc Carrique, Hemalatha Balaram and Nushin Aghajari
Biomolecules 2022, 12(7), 871; https://doi.org/10.3390/biom12070871 - 23 Jun 2022
Cited by 1 | Viewed by 2149
Abstract
Glutamine amidotransferases, enzymes that transfer nitrogen from Gln to various cellular metabolites, are modular, with the amidotransferase (GATase) domain hydrolyzing Gln, generating ammonia and the acceptor domain catalyzing the addition of nitrogen onto its cognate substrate. GMP synthetase (GMPS), an enzyme in the [...] Read more.
Glutamine amidotransferases, enzymes that transfer nitrogen from Gln to various cellular metabolites, are modular, with the amidotransferase (GATase) domain hydrolyzing Gln, generating ammonia and the acceptor domain catalyzing the addition of nitrogen onto its cognate substrate. GMP synthetase (GMPS), an enzyme in the de novo purine nucleotide biosynthetic pathway, is a glutamine amidotransferase that catalyzes the synthesis of GMP from XMP. The reaction involves activation of XMP though adenylation by ATP in the ATP pyrophosphatase (ATPPase) active site, followed by channeling and attack of NH3 generated in the GATase pocket. This complex chemistry entails co-ordination of activity across the active sites, allosteric activation of the GATase domain to modulate Gln hydrolysis and channeling of ammonia from the GATase to the acceptor active site. Functional GMPS dimers associate through the dimerization domain. The crystal structure of the Gln-bound complex of Plasmodium falciparum GMPS (PfGMPS) for the first time revealed large-scale domain rotation to be associated with catalysis and leading to the juxtaposition of two otherwise spatially distal cysteinyl (C113/C337) residues. In this manuscript, we report on an unusual structural variation in the crystal structure of the C89A/C113A PfGMPS double mutant, wherein a larger degree of domain rotation has led to the dissociation of the dimeric structure. Furthermore, we report a hitherto overlooked signature motif tightly related to catalysis. Full article
(This article belongs to the Special Issue New Insights into Conformational Changes in Glutamine Amidotransferases)
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Review

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23 pages, 5230 KiB  
Review
GMP Synthetase: Allostery, Structure, and Function
by Lionel Ballut, Sébastien Violot, Sanjeev Kumar, Nushin Aghajari and Hemalatha Balaram
Biomolecules 2023, 13(9), 1379; https://doi.org/10.3390/biom13091379 - 12 Sep 2023
Cited by 1 | Viewed by 2215
Abstract
Glutamine amidotransferases (GATs) catalyze the hydrolysis of glutamine and transfer the generated ammonia to diverse metabolites. The two catalytic activities, glutaminolysis and the subsequent amination of the acceptor substrate, happen in two distinct catalytic pockets connected by a channel that facilitates the movement [...] Read more.
Glutamine amidotransferases (GATs) catalyze the hydrolysis of glutamine and transfer the generated ammonia to diverse metabolites. The two catalytic activities, glutaminolysis and the subsequent amination of the acceptor substrate, happen in two distinct catalytic pockets connected by a channel that facilitates the movement of ammonia. The de novo pathway for the synthesis of guanosine monophosphate (GMP) from xanthosine monophosphate (XMP) is enabled by the GAT GMP synthetase (GMPS). In most available crystal structures of GATs, the ammonia channel is evident in their native state or upon ligand binding, providing molecular details of the conduit. In addition, conformational changes that enable the coordination of the two catalytic chemistries are also informed by the available structures. In contrast, despite the first structure of a GMPS being published in 1996, the understanding of catalysis in the acceptor domain and inter-domain crosstalk became possible only after the structure of a glutamine-bound mutant of Plasmodium falciparum GMPS was determined. In this review, we present the current status of our understanding of the molecular basis of catalysis in GMPS, becoming the first comprehensive assessment of the biochemical function of this intriguing enzyme. Full article
(This article belongs to the Special Issue New Insights into Conformational Changes in Glutamine Amidotransferases)
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27 pages, 7574 KiB  
Review
GTP-Dependent Regulation of CTP Synthase: Evolving Insights into Allosteric Activation and NH3 Translocation
by Stephen L. Bearne, Chen-Jun Guo and Ji-Long Liu
Biomolecules 2022, 12(5), 647; https://doi.org/10.3390/biom12050647 - 29 Apr 2022
Cited by 10 | Viewed by 3975
Abstract
Cytidine-5′-triphosphate (CTP) synthase (CTPS) is the class I glutamine-dependent amidotransferase (GAT) that catalyzes the last step in the de novo biosynthesis of CTP. Glutamine hydrolysis is catalyzed in the GAT domain and the liberated ammonia is transferred via an intramolecular tunnel to the [...] Read more.
Cytidine-5′-triphosphate (CTP) synthase (CTPS) is the class I glutamine-dependent amidotransferase (GAT) that catalyzes the last step in the de novo biosynthesis of CTP. Glutamine hydrolysis is catalyzed in the GAT domain and the liberated ammonia is transferred via an intramolecular tunnel to the synthase domain where the ATP-dependent amination of UTP occurs to form CTP. CTPS is unique among the glutamine-dependent amidotransferases, requiring an allosteric effector (GTP) to activate the GAT domain for efficient glutamine hydrolysis. Recently, the first cryo-electron microscopy structure of Drosophila CTPS was solved with bound ATP, UTP, and, notably, GTP, as well as the covalent adduct with 6-diazo-5-oxo-l-norleucine. This structural information, along with the numerous site-directed mutagenesis, kinetics, and structural studies conducted over the past 50 years, provide more detailed insights into the elaborate conformational changes that accompany GTP binding at the GAT domain and their contribution to catalysis. Interactions between GTP and the L2 loop, the L4 loop from an adjacent protomer, the L11 lid, and the L13 loop (or unique flexible “wing” region), induce conformational changes that promote the hydrolysis of glutamine at the GAT domain; however, direct experimental evidence on the specific mechanism by which these conformational changes facilitate catalysis at the GAT domain is still lacking. Significantly, the conformational changes induced by GTP binding also affect the assembly and maintenance of the NH3 tunnel. Hence, in addition to promoting glutamine hydrolysis, the allosteric effector plays an important role in coordinating the reactions catalyzed by the GAT and synthase domains of CTPS. Full article
(This article belongs to the Special Issue New Insights into Conformational Changes in Glutamine Amidotransferases)
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