Guarding the gateway to histidine biosynthesis in plants: Medicago truncatula ATP-phosphoribosyltransferase in relaxed and tense states
In the first committed step of histidine biosynthesis, adenosine 5'-triphosphate (ATP) and 5-phosphoribosyl-α1-pyrophosphate (PRPP), in the presence of ATP phosphoribosyltransferase (ATP-PRT, EC 2.4.2.17), yield phosphoribosyl-ATP. ATP-PRTs are subject to feedback inhibition by histidine that allosterically binds between the regulatory domains. Histidine biosynthetic pathways of bacteria, lower eukaryotes, and plants are considered promising targets for the design of antibiotics, antifungal agents, and herbicides because higher organisms are histidine heterotrophs. Plant ATP-PRTs are similar to one of the two types o...
Source: Biochemical Journal - August 31, 2018 Category: Biochemistry Authors: Ruszkowski, M. Tags: Research Articles Source Type: research
Structural and functional characterization of the RBBP4-ZNF827 interaction and its role in NuRD recruitment to telomeres
The nucleosome remodeling and histone deacetylase (NuRD) complex is an essential multi-subunit protein complex that regulates higher-order chromatin structure. Cancers that use the alternative lengthening of telomere (ALT) pathway of telomere maintenance recruit NuRD to their telomeres. This interaction is mediated by the N-terminal domain of the zinc-finger protein ZNF827. NuRD–ZNF827 plays a vital role in the ALT pathway by creating a molecular platform for recombination-mediated repair. Disruption of NuRD binding results in loss of ALT cell viability. Here, we present the crystal structure of the NuRD subunit RBBP...
Source: Biochemical Journal - August 31, 2018 Category: Biochemistry Authors: Yang, S. F., Sun, A.-a., Shi, Y., Li, F., Pickett, H. A. Tags: Research Articles Source Type: research
Lead induces the up-regulation of the protein arginine methyltransferase 5 possibly by its promoter demethylation
The studies on lead (Pb) exposure linking to epigenetic modulations are caused by its differential actions on global DNA methylation and histone modifications. These epigenetic changes may result in increased accessibility of the transcription factors to promoter DNA-binding elements leading to activation and expression of the gene. The protein arginine methyltransferase 5 (PRMT5) and its partner methylosome protein 50 (MEP50) together catalyze the mono- and symmetric dimethylation of arginine residues in many histone and non-histone protein substrates. Moreover, it is overexpressed in many forms of cancer. In the present ...
Source: Biochemical Journal - August 30, 2018 Category: Biochemistry Authors: Ghosh, K., Chatterjee, B., Kanade, S. R. Tags: Research Articles Source Type: research
Toxicity of dihydroxyacetone is exerted through the formation of methylglyoxal in Saccharomyces cerevisiae: effects on actin polarity and nuclear division
Dihydroxyacetone (DHA) is the smallest ketotriose, and it is utilized by many organisms as an energy source. However, at higher concentrations, DHA becomes toxic towards several organisms including the budding yeast Saccharomyces cerevisiae. In the present study, we show that DHA toxicity is due to its spontaneous conversion to methylglyoxal (MG) within yeast cells. A mutant defective in MG-metabolizing enzymes (glo1gre2gre3) exhibited higher susceptibility to DHA. Intracellular MG levels increased following the treatment of glo1gre2gre3 cells with DHA. We previously reported that MG depolarized the actin cytoskeleton and ...
Source: Biochemical Journal - August 30, 2018 Category: Biochemistry Authors: Nomura, W., Aoki, M., Inoue, Y. Tags: Research Articles Source Type: research
Arabidopsis calcineurin B-like proteins differentially regulate phosphorylation activity of CBL-interacting protein kinase 9
Calcium (Ca2+) is a versatile and ubiquitous second messenger in all eukaryotes including plants. In response to various stimuli, cytosolic calcium concentration ([Ca2+]cyt) is increased, leading to activation of Ca2+ sensors including Arabidopsis calcineurin B-like proteins (CBLs). CBLs interact with CBL-interacting protein kinases (CIPKs) to form CBL–CIPK complexes and transduce the signal downstream in the signalling pathway. Although there are many reports on the regulation of downstream targets by CBL–CIPK module, knowledge about the regulation of upstream components by individual CIPKs is inadequate. In t...
Source: Biochemical Journal - August 30, 2018 Category: Biochemistry Authors: Yadav, A. K., Jha, S. K., Sanyal, S. K., Luan, S., Pandey, G. K. Tags: Research Articles Source Type: research
Force-activated catalytic pathway accelerates bacterial adhesion against flow
Mechanical cues often influence the factors affecting the transition states of catalytic reactions and alter the activation pathway. However, tracking the real-time dynamics of such activation pathways is limited. Using single-molecule trapping of reaction intermediates, we developed a method that enabled us to perform one reaction at one site and simultaneously study the real-time dynamics of the catalytic pathway. Using this, we showed single-molecule calligraphy at nanometer resolution and deciphered the mechanism of the sortase A enzymatic reaction that, counter-intuitively, accelerates bacterial adhesion under shear t...
Source: Biochemical Journal - August 30, 2018 Category: Biochemistry Authors: Hazra, J. P., Arora, N., Sagar, A., Srinivasan, S., Chaudhuri, A., Rakshit, S. Tags: Research Articles Source Type: research
A role for trypanosomatid aldo-keto reductases in methylglyoxal, prostaglandin and isoprostane metabolism
Trypanosomatid parasites are the infectious agents causing Chagas disease, visceral and cutaneous leishmaniasis and human African trypanosomiasis. Recent work of others has implicated an aldo-keto reductase (AKR) in the susceptibility and resistance of Trypanosoma cruzi to benznidazole, a drug used to treat Chagas disease. Here, we show that TcAKR and homologues in the related parasites Trypanosoma brucei and Leishmania donovani do not reductively activate monocyclic (benznidazole, nifurtimox and fexinidazole) or bicyclic nitro-drugs such as PA-824. Rather, these enzymes metabolise a variety of toxic ketoaldehydes, such as...
Source: Biochemical Journal - August 30, 2018 Category: Biochemistry Authors: Roberts, A. J., Dunne, J., Scullion, P., Norval, S., Fairlamb, A. H. Tags: Research Articles Source Type: research
An appeal to magic? The discovery of a non-enzymatic metabolism and its role in the origins of life
Until recently, prebiotic precursors to metabolic pathways were not known. In parallel, chemistry achieved the synthesis of amino acids and nucleotides only in reaction sequences that do not resemble metabolic pathways, and by using condition step changes, incompatible with enzyme evolution. As a consequence, it was frequently assumed that the topological organisation of the metabolic pathway has formed in a Darwinian process. The situation changed with the discovery of a non-enzymatic glycolysis and pentose phosphate pathway. The suite of metabolism-like reactions is promoted by a metal cation, (Fe(II)), abundant in Arche...
Source: Biochemical Journal - August 30, 2018 Category: Biochemistry Authors: Ralser, M. Tags: Review Articles Source Type: research
Stimulation of the ATPase activity of Hsp90 by zerumbone modification of its cysteine residues destabilizes its clients and causes cytotoxicity
Hsp90 is an ATP-dependent molecular chaperone that assists folding and conformational maturation/maintenance of many proteins. It is a potential cancer drug target because it chaperones oncoproteins. A prokaryotic homolog of Hsp90 (HtpG) is essential for thermo-tolerance in some bacteria and virulence of zoonotic pathogens. To identify a new class of small molecules which target prokaryotic and eukaryotic Hsp90s, we studied the effects of a naturally occurring cyclic sesquiterpene, zerumbone, which inhibits proliferation of a wide variety of tumor cells, on the activity of Hsp90. Zerumbone enhanced the ATPase activity of c...
Source: Biochemical Journal - August 16, 2018 Category: Biochemistry Authors: Nakamoto, H., Amaya, Y., Komatsu, T., Suzuki, T., Dohmae, N., Nakamura, Y., Jantan, I., Miyata, Y. Tags: Research Articles Source Type: research
Evidence for substrate-assisted catalysis in N-acetylphosphoglucosamine mutase
N-acetylphosphoglucosamine mutase (AGM1) is a key component of the hexosamine biosynthetic pathway that produces UDP-GlcNAc, an essential precursor for a wide range of glycans in eukaryotes. AGM belongs to the α-d-phosphohexomutase metalloenzyme superfamily and catalyzes the interconversion of N-acetylglucosamine-6-phosphate (GlcNAc-6P) to N-acetylglucosamine-1-phosphate (GlcNAc-1P) through N-acetylglucosamine-1,6-bisphosphate (GlcNAc-1,6-bisP) as the catalytic intermediate. Although there is an understanding of the phosphoserine-dependent catalytic mechanism at enzymatic and structural level, the identity of the req...
Source: Biochemical Journal - August 16, 2018 Category: Biochemistry Authors: Raimi, O. G., Hurtado-Guerrero, R., van Aalten, D. M. F. Tags: Research Articles Source Type: research
Glycans and glycosaminoglycans in neurobiology: key regulators of neuronal cell function and fate
The aim of the present study was to examine the roles of l-fucose and the glycosaminoglycans (GAGs) keratan sulfate (KS) and chondroitin sulfate/dermatan sulfate (CS/DS) with selected functional molecules in neural tissues. Cell surface glycans and GAGs have evolved over millions of years to become cellular mediators which regulate fundamental aspects of cellular survival. The glycocalyx, which surrounds all cells, actuates responses to growth factors, cytokines and morphogens at the cellular boundary, silencing or activating downstream signaling pathways and gene expression. In this review, we have focused on interactions...
Source: Biochemical Journal - August 16, 2018 Category: Biochemistry Authors: Hayes, A. J., Melrose, J. Tags: Review Articles Source Type: research
The cloak, dagger, and shield: proteases in plant-pathogen interactions
Plants sense the presence of pathogens or pests through the recognition of evolutionarily conserved microbe- or herbivore-associated molecular patterns or specific pathogen effectors, as well as plant endogenous danger-associated molecular patterns. This sensory capacity is largely mediated through plasma membrane and cytosol-localized receptors which trigger complex downstream immune signaling cascades. As immune signaling outputs are often associated with a high fitness cost, precise regulation of this signaling is critical. Protease-mediated proteolysis represents an important form of pathway regulation in this context....
Source: Biochemical Journal - August 16, 2018 Category: Biochemistry Authors: Hou, S., Jamieson, P., He, P. Tags: Review Articles Source Type: research
Mutation of G51 in SepF impairs FtsZ assembly promoting ability of SepF and retards the division of Mycobacterium smegmatis cells
The role of FtsZ-associated proteins in the regulation of the assembly dynamics of Mycobacterium smegmatis FtsZ is not clear. In this work, we examined the effect of M. smegmatis SepF on the assembly and stability of M. smegmatis FtsZ polymers. We discovered a single dominant point mutation in SepF (G51D or G51R) that renders the protein inactive. SepF promoted the polymerization of FtsZ, induced the bundling of FtsZ filaments, stabilized FtsZ filaments and reduced the GTPase activity of FtsZ. Surprisingly, both G51D-SepF and G51R-SepF neither stabilized FtsZ filaments nor showed a discernable effect on the GTPase activity...
Source: Biochemical Journal - August 14, 2018 Category: Biochemistry Authors: Bhattacharya, D., Sinha, K., Panda, D. Tags: Research Articles Source Type: research
Structure, interactions and action of Mycobacterium tuberculosis 3-hydroxyisobutyric acid dehydrogenase
Biochemical and crystallographic studies on Mycobacterium tuberculosis 3-hydroxyisobutyric acid dehydrogenase (MtHIBADH), a member of the 3-hydroxyacid dehydrogenase superfamily, have been carried out. Gel filtration and blue native PAGE of MtHIBADH show that the enzyme is a dimer. The enzyme preferentially uses NAD+ as the cofactor and is specific to S-hydroxyisobutyric acid (HIBA). It can also use R-HIBA, l-serine and 3-hydroxypropanoic acid (3-HP) as substrates, but with much less efficiency. The pH optimum for activity is ~11. Structures of the native enzyme, the holoenzyme, binary complexes with NAD+, S-HIBA, R-HIBA, ...
Source: Biochemical Journal - August 14, 2018 Category: Biochemistry Authors: Srikalaivani, R., Singh, A., Vijayan, M., Surolia, A. Tags: Research Articles Source Type: research
New tools for evaluating protein tyrosine sulfation: tyrosylprotein sulfotransferases (TPSTs) are novel targets for RAF protein kinase inhibitors
Protein tyrosine sulfation is a post-translational modification best known for regulating extracellular protein–protein interactions. Tyrosine sulfation is catalysed by two Golgi-resident enzymes termed tyrosylprotein sulfotransferases (TPSTs) 1 and 2, which transfer sulfate from the cofactor PAPS (3'-phosphoadenosine 5'-phosphosulfate) to a context-dependent tyrosine in a protein substrate. A lack of quantitative tyrosine sulfation assays has hampered the development of chemical biology approaches for the identification of small-molecule inhibitors of tyrosine sulfation. In the present paper, we describe the develop...
Source: Biochemical Journal - August 14, 2018 Category: Biochemistry Authors: Byrne, D. P., Li, Y., Ngamlert, P., Ramakrishnan, K., Eyers, C. E., Wells, C., Drewry, D. H., Zuercher, W. J., Berry, N. G., Fernig, D. G., Eyers, P. A. Tags: Research Articles Source Type: research
