Chris Whittington, Ajay Sharma, S Gage Hill, Anthony T Iavarone, Brian M Hoffman, Adam R Offenbacher
Lipoxygenases (LOXs) from pathogenic fungi are potential therapeutic targets for defense against plant and select human diseases. In contrast to the canonical LOXs in plants and animals, fungal LOXs are unique in having appended N -linked glycans. Such important post-translational modifications (PTMs) endow proteins with altered structure, stability, and/or function. In this study, we present the structural and functional outcomes of removing or altering these surface carbohydrates on the LOX from the devastating rice blast fungus, M...
May 1, 2024: Biochemistry
Taichi Kamo, Keiichi Kuroda, Saki Nimura, Yan Guo, Shota Kondo, Michiyoshi Nukaga, Tyuji Hoshino
Metallo-β-lactamases (MBL) deactivate β-lactam antibiotics through a catalytic reaction caused by two zinc ions at the active center. Since MBLs deteriorate a wide range of antibiotics, they are dangerous factors for bacterial multidrug resistance. In this work, organic synthesis, computational design, and crystal structure analysis were performed to obtain potent MBL inhibitors based on a previously identified hit compound. The hit compound comprised 3,4-dihydro-2(1H)-quinolinone linked with a phenyl-ether-methyl group via a thiazole ring...
May 1, 2024: Biochemistry
Chang-Ju Lee, Bo-Hee Choi, So-Sun Kim, David Nahm-Joon Kim, Tae-Hwan Kim, Jeong-Mo Choi, Youngshang Pak, Jang-Su Park
In this study, we investigated the trimerization mechanism and structure of heat shock factor 1 (HSF1) using western blotting, tryptophan (Trp) fluorescence spectroscopy, and molecular modeling. First, we examined the DNA-binding domains of human ( Homo sapiens ), goldfish ( Carassius auratus ), and walleye pollock ( Gadus chalcogrammus ) HSF1s by mutating key residues (36 and 103) that are thought to directly affect trimer formation. Human, goldfish, and walleye pollock HSF1s contain cysteine at residue 36 but cysteine (C), tyrosine (Y), and phenylalanine (F), respectively, at residue 103...
April 30, 2024: Biochemistry
Arash Samadi, Samuel Tanoeyadi, Takeshi Tsunoda, Philip J Proteau, Taifo Mahmud
Sedoheptulose 7-phosphate (SH7P) cyclases are a subset of sugar phosphate cyclases that are known to catalyze the first committed step in many biosynthetic pathways in primary and secondary metabolism. Among them are 2- epi -5- epi -valiolone synthase (EEVS) and 2- epi -valiolone synthase (EVS), two closely related SH7P cyclases that catalyze the conversion of SH7P to 2- epi -5- epi -valiolone and 2- epi -valiolone, respectively. However, how these two homologous enzymes use a common substrate to produce stereochemically different products is unknown...
April 30, 2024: Biochemistry
Samuel Cashman-Kadri, Patrick Lagüe, Muriel Subirade, Ismail Fliss, Lucie Beaulieu
Interactions between SJGAP (skipjack tuna GAPDH-related antimicrobial peptide) and four analogs thereof with model bacterial membranes were studied using Fourier-transform infrared spectroscopy (FTIR) and molecular dynamics (MD) simulations. MD trajectory analyses showed that the N-terminal segment of the peptide analogs has many contacts with the polar heads of membrane phospholipids, while the central α helix interacts strongly with the hydrophobic core of the membranes. The peptides also had a marked influence on the wave numbers associated with the phase transition of phospholipids organized as liposomes in both the interface and aliphatic chain regions of the infrared spectra, supporting the interactions observed in the MD trajectories...
April 29, 2024: Biochemistry
Min-Li Zhan, Xi Zhao, Xiao-Dan Li, Zi-Zhu Tan, Qian-Zhao Xu, Ming Zhou, Kai-Hong Zhao
As plant photoreceptors, phytochromes are capable of detecting red light and far-red light, thereby governing plant growth. All2699 is a photoreceptor found in Nostoc sp. PCC7120 that specifically responds to red light and far-red light. All2699g1g2 is a truncated protein carrying the first and second GAF (cGMP phosphodiesterase/adenylyl cyclase/FhlA) domains of All2699. In this study, we found that, upon exposure to red light, the protein underwent aggregation, resulting in the formation of protein aggregates...
April 29, 2024: Biochemistry
Collin J Steen, Jens Niklas, Oleg G Poluektov, Richard D Schaller, Graham R Fleming, Lisa M Utschig
A central goal of photoprotective energy dissipation processes is the regulation of singlet oxygen (1 O2 *) and reactive oxygen species in the photosynthetic apparatus. Despite the involvement of 1 O2 * in photodamage and cell signaling, few studies directly correlate 1 O2 * formation to nonphotochemical quenching (NPQ) or lack thereof. Here, we combine spin-trapping electron paramagnetic resonance (EPR) and time-resolved fluorescence spectroscopies to track in real time the involvement of 1 O2 * during photoprotection in plant thylakoid membranes...
April 28, 2024: Biochemistry
Corey Thomas, Lisbeth Avalos-Irving, Jorge Victorino, Sydney Green, Morgan Andrews, Naisha Rodrigues, Sarah Ebirim, Ayden Mudd, Jamie B Towle-Weicksel
DNA polymerase θ (Pol θ or POLQ) is primarily involved in repairing double-stranded breaks in DNA through an alternative pathway known as microhomology-mediated end joining (MMEJ) or theta-mediated end joining (TMEJ). Unlike other DNA repair polymerases, Pol θ is thought to be highly error-prone yet critical for cell survival. We have identified several POLQ gene variants from human melanoma tumors that experience altered DNA polymerase activity, including a propensity for incorrect nucleotide selection and reduced polymerization rates compared to WT Pol θ...
April 26, 2024: Biochemistry
Tania Churasacari Vinces, Anacleto Silva de Souza, Cecília F Carvalho, Aline Biazola Visnardi, Raphael D Teixeira, Edgar E Llontop, Beatriz Aparecida Passos Bismara, Elisabete J Vicente, José O Pereira, Robson Francisco de Souza, Mauricio Yonamine, Sandro Roberto Marana, Chuck Shaker Farah, Cristiane R Guzzo
Herein, we present a novel esterase enzyme, Ade1, isolated from a metagenomic library of Amazonian dark earths soils, demonstrating its broad substrate promiscuity by hydrolyzing ester bonds linked to aliphatic groups. The three-dimensional structure of the enzyme was solved in the presence and absence of substrate (tributyrin), revealing its classification within the α/β-hydrolase superfamily. Despite being a monomeric enzyme, enzymatic assays reveal a cooperative behavior with a sigmoidal profile (initial velocities vs substrate concentrations)...
April 26, 2024: Biochemistry
Angela M Develin, Brian Fuglestad
As a key component for NADPH oxidase 2 (NOX2) activation, the peripheral membrane protein p47phox translocates a cytosolic activating complex to the membrane through its PX domain. This study elucidates a potential regulatory mechanism of p47phox recruitment and NOX2 activation by inositol hexaphosphate (IP6). Through NMR, fluorescence polarization, and FRET experimental results, IP6 is shown to be capable of breaking the lipid binding and membrane anchoring events of p47phox -PX with low micromolar potency...
April 26, 2024: Biochemistry
Shahid A Malik, Somnath Mondal, Hanudatta S Atreya
Parkinson's disease (PD) is characterized by the toxic oligomeric and fibrillar phases formed by monomeric alpha-synuclein (α-syn). Certain nanoparticles have been demonstrated to promote protein aggregation, while other nanomaterials have been found to prevent the process. In the current work, we use nuclear magnetic resonance spectroscopy in conjunction with isothermal titration calorimetry to investigate the cause and mechanism of these opposing effects at the amino acid protein level. The interaction of α-syn with two types of nanomaterials was considered: citrate-capped gold nanoparticles (AuNPs) and graphene oxide (GO)...
April 26, 2024: Biochemistry
Diana L Cudia, Effibe O Ahoulou, Aritra Bej, Annika N Janssen, Alexander Scholten, Karl-W Koch, James B Ames
Guanylate cyclase activating protein-5 (GCAP5) in zebrafish photoreceptors promotes the activation of membrane receptor retinal guanylate cyclase (GC-E). Previously, we showed the R22A mutation in GCAP5 (GCAP5R22A ) abolishes dimerization of GCAP5 and activates GC-E by more than 3-fold compared to that of wild-type GCAP5 (GCAP5WT ). Here, we present ITC, NMR, and functional analysis of GCAP5R22A to understand how R22A causes a decreased dimerization affinity and increased cyclase activation. ITC experiments reveal GCAP5R22A binds a total of 3 Ca2+ , including two sites in the nanomolar range followed by a single micromolar site...
April 25, 2024: Biochemistry
Charu Thapliyal, Rajesh Mishra
HdeA and HdeB are dimeric ATP-independent acid-stress chaperones, which protect the periplasmic proteins of enteric bacteria at pH 2.0 and 4.0, respectively, during their passage through the acidic environment of the mammalian stomach. Despite being structurally similar, they exhibit distinct functional pH optima and conformational prerequisite for their chaperone action. HdeA undergoes a dimer-to-monomer transition at pH 2.0, whereas HdeB remains dimeric at pH 4.0. The monomerization of HdeA exposes its hydrophobic motifs, which facilitates its interaction with the partially folded substrates...
April 19, 2024: Biochemistry
Megh R Bhatt, Himal K Ganguly, Neal J Zondlo
Acyl capping groups stabilize α-helices relative to free N-termini by providing one additional C═O i ···H i +4 -N hydrogen bond. The electronic properties of acyl capping groups might also directly modulate α-helix stability: electron-rich N-terminal acyl groups could stabilize the α-helix by strengthening both i / i + 4 hydrogen bonds and i / i + 1 n → π* interactions. This hypothesis was tested in peptides X-AKAAAAKAAAAKAAGY-NH2 , where X = different acyl groups...
April 16, 2024: Biochemistry
Josephine C Ferreon, Hai Minh Ta, Hyosuk Yun, Kyoung-Jae Choi, My Diem Quan, Phoebe S Tsoi, Choel Kim, Chul Won Lee, Allan Chris M Ferreon
NANOG protein levels correlate with stem cell pluripotency. NANOG concentrations fluctuate constantly with low NANOG levels leading to spontaneous cell differentiation. Previous literature implicated Pin1, a phosphorylation-dependent prolyl isomerase, as a key player in NANOG stabilization. Here, using NMR spectroscopy, we investigate the molecular interactions of Pin1 with the NANOG unstructured N-terminal domain that contains a PEST sequence with two phosphorylation sites. Phosphorylation of NANOG PEST peptides increases affinity to Pin1...
April 15, 2024: Biochemistry
Jessica Liebau, Bethany F Laatsch, Joshua Rusnak, Keegan Gunderson, Brianna Finke, Kassandra Bargender, Alex Narkiewicz-Jodko, Katelyn Weeks, Murphi T Williams, Irina Shulgina, Karin Musier-Forsyth, Sudeep Bhattacharyya, Sanchita Hati
Polyethylene glycol (PEG) is a flexible, nontoxic polymer commonly used in biological and medical research, and it is generally regarded as biologically inert. PEG molecules of variable sizes are also used as crowding agents to mimic intracellular environments. A recent study with PEG crowders revealed decreased catalytic activity of Escherichia coli prolyl-tRNA synthetase (Ec ProRS), where the smaller molecular weight PEGs had the maximum impact. The molecular mechanism of the crowding effects of PEGs is not clearly understood...
April 12, 2024: Biochemistry
Jianjun Cao, Matthew J Belousoff, Radostin Danev, Arthur Christopoulos, Denise Wootten, Patrick M Sexton
Inhibition of calcitonin gene-related peptide (CGRP) or its cognate CGRP receptor (CGRPR) has arisen as a major breakthrough in the treatment of migraine. However, a second CGRP-responsive receptor exists, the amylin (Amy) 1 receptor (AMY1 R), yet its involvement in the pathology of migraine is poorly understood. AMY1 R and CGRPR are heterodimers consisting of receptor activity-modifying protein 1 (RAMP1) with the calcitonin receptor (CTR) and the calcitonin receptor-like receptor (CLR), respectively. Here, we present the structure of AMY1 R in complex with CGRP and Gs protein and compare it with the reported structures of the AMY1 R complex with rat amylin (rAmy) and the CGRPR in complex with CGRP...
April 11, 2024: Biochemistry
Wiktoria Brytan, Kim Shortall, Francisco Duarte, Tewfik Soulimane, Luis Padrela
Aldehyde dehydrogenase enzymes (ALDHs) are widely studied for their roles in disease propagation and cell metabolism. Their use in biocatalysis applications, for the conversion of aldehydes to carboxylic acids, has also been recognized. Understanding the structural features and functions of both prokaryotic and eukaryotic ALDHs is key to uncovering novel applications of the enzyme and probing its role in disease propagation. The thermostable enzyme ALDH Tt originating from Thermus thermophilus , strain HB27, possesses a unique extension of its C-terminus, which has been evolutionarily excluded from mesophilic counterparts and other thermophilic enzymes in the same genus...
April 11, 2024: Biochemistry
Swapna Bera, Rajiv K Kar, Susanta Mondal, Kalipada Pahan, Anirban Bhunia
No abstract text is available yet for this article.
April 10, 2024: Biochemistry
Himal K Ganguly, Brice A Ludwig, Caitlin M Tressler, Megh R Bhatt, Anil K Pandey, Caitlin M Quinn, Shi Bai, Glenn P A Yap, Neal J Zondlo
Despite the importance of proline conformational equilibria ( trans versus cis amide and exo versus endo ring pucker) on protein structure and function, there is a lack of convenient ways to probe proline conformation. 4,4-Difluoroproline (Dfp) was identified to be a sensitive 19 F NMR-based probe of proline conformational biases and cis-trans isomerism. Within model compounds and disordered peptides, the diastereotopic fluorines of Dfp exhibit similar chemical shifts (ΔδFF = 0-3 ppm) when a trans X-Dfp amide bond is present...
April 10, 2024: Biochemistry
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