Full Text Journal Articles by
Author John B Bruning

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To Be, or Not to Be, an Inhibitor: A Comparison of Azole Interactions with and Oxidation by a Cytochrome P450 Enzyme.

Matthew N Podgorski, Tom Coleman, Peter D Giang, C Ruth Wang, John B Bruning, Paul V Bernhardt, James J De Voss, Stephen G Bell,

The cytochrome P450 (CYP) superfamily of heme monooxygenases is involved in a range of important chemical biotransformations across nature. Azole-containing molecules have been developed as drugs that bind to the heme center of these enzymes, inhibiting their function. The optical spectrum of CYP enzymes after the addition of these inhibitors ... Read more >>

Inorg Chem (Inorganic chemistry)
[2022, 61(1):236-245]

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The Stereoselective Oxidation of para-Substituted Benzenes by a Cytochrome P450 Biocatalyst.

Rebecca R Chao, Ian C-K Lau, Tom Coleman, Luke R Churchman, Stella A Child, Joel H Z Lee, John B Bruning, James J De Voss, Stephen G Bell,

The serine 244 to aspartate (S244D) variant of the cytochrome P450 enzyme CYP199A4 was used to expand its substrate range beyond benzoic acids. Substrates, in which the carboxylate group of the benzoic acid moiety is replaced were oxidised with high activity by the S244D mutant (product formation rates >60 nmol.(nmol-CYP)<sup>-1</sup> .min<sup>-1</sup> ... Read more >>

Chemistry (Chemistry (Weinheim an der Bergstrasse, Germany))
[2021, 27(59):14765-14777]

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Inhibition of Mycobacterium tuberculosis Dethiobiotin Synthase (MtDTBS): Toward Next-Generation Antituberculosis Agents.

Nicholas C Schumann, Kwang Jun Lee, Andrew P Thompson, Wanisa Salaemae, Jordan L Pederick, Thomas Avery, Birgit I Gaiser, James Hodgkinson-Bean, Grant W Booker, Steven W Polyak, John B Bruning, Kate L Wegener, Andrew D Abell,

<i>Mycobacterium tuberculosis</i> dethiobiotin synthase (<i>Mt</i>DTBS) is a crucial enzyme involved in the biosynthesis of biotin in the causative agent of tuberculosis, <i>M. tuberculosis</i>. Here, we report a binder of <i>Mt</i>DTBS, cyclopentylacetic acid <b>2</b> (<i>K</i><sub>D</sub> = 3.4 ± 0.4 mM), identified <i>via</i> <i>in silico</i> screening. X-ray crystallography showed that <b>2</b> binds ... Read more >>

ACS Chem Biol (ACS chemical biology)
[2021, 16(11):2339-2347]

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A cell permeable bimane-constrained PCNA-interacting peptide.

Aimee J Horsfall, Beth A Vandborg, Zoya Kikhtyak, Denis B Scanlon, Wayne D Tilley, Theresa E Hickey, John B Bruning, Andrew D Abell,

The human sliding clamp protein known as proliferating cell nuclear antigen (PCNA) orchestrates DNA-replication and -repair and as such is an ideal therapeutic target for proliferative diseases, including cancer. Peptides derived from the human p21 protein bind PCNA with high affinity <i>via</i> a 3<sub>10</sub>-helical binding conformation and are known to ... Read more >>

RSC Chem Biol (RSC chemical biology)
[2021, 2(5):1499-1508]

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Engineering potassium activation into biosynthetic thiolase.

Andrew C Marshall, John B Bruning,

Activation of enzymes by monovalent cations (M+) is a widespread phenomenon in biology. Despite this, there are few structure-based studies describing the underlying molecular details. Thiolases are a ubiquitous and highly conserved family of enzymes containing both K+-activated and K+-independent members. Guided by structures of naturally occurring K+-activated thiolases, we ... Read more >>

Biochem J (The Biochemical journal)
[2021, 478(15):3047-3062]

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The therapeutic potential of inhibiting PPARγ phosphorylation to treat type 2 diabetes.

Rebecca L Frkic, Katharina Richter, John B Bruning,

A promising approach for treating type 2 diabetes mellitus (T2DM) is to target the Peroxisome Proliferator-Activated Receptor γ (PPARγ) transcription factor, which regulates the expression of proteins critical for T2DM. Mechanisms involved in PPARγ signaling are poorly understood, yet globally increasing T2DM prevalence demands improvements in drug design. Synthetic, nonactivating ... Read more >>

J Biol Chem (The Journal of biological chemistry)
[2021, 297(3):101030]

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Approaches to Introduce Helical Structure in Cysteine-Containing Peptides with a Bimane Group.

Aimee J Horsfall, Daniel P McDougal, Denis B Scanlon, John B Bruning, Andrew D Abell,

An i-i+4 or i-i+3 bimane-containing linker was introduced into a peptide known to target Estrogen Receptor alpha (ERα), in order to stabilise an α-helical geometry. These macrocycles were studied by CD and NMR to reveal the i-i+4 constrained peptide adopts a 3<sub>10</sub> -helical structure in solution, and an α-helical conformation ... Read more >>

Chembiochem (Chembiochem : a European journal of chemical biology)
[2021, 22(17):2711-2720]

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Constitutive JAK/STAT signaling is the primary mechanism of resistance to JAKi in TYK2-rearranged acute lymphoblastic leukemia.

Paniz Tavakoli Shirazi, Laura N Eadie, Elyse C Page, Susan L Heatley, John B Bruning, Deborah L White,

Activating TYK2-rearrangements have recently been identified and implicated in the leukemogenesis of high-risk acute lymphoblastic leukemia (HR-ALL) cases. Pre-clinical studies indicated the JAK/TYK2 inhibitor (JAKi), cerdulatinib, as a promising therapeutic against TYK2-rearranged ALL, attenuating the constitutive JAK/STAT signaling resulting from the TYK2 fusion protein. However, following a period of clinical ... Read more >>

Cancer Lett (Cancer letters)
[2021, 512:28-37]

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Simplified heavy-atom derivatization of protein structures via co-crystallization with the MAD tetragon tetrabromoterephthalic acid.

Jia Q Truong, Stephanie Nguyen, John B Bruning, Keith E Shearwin,

The phase problem is a persistent bottleneck that impedes the structure-determination pipeline and must be solved to obtain atomic resolution crystal structures of macromolecules. Although molecular replacement has become the predominant method of solving the phase problem, many scenarios still exist in which experimental phasing is needed. Here, a proof-of-concept ... Read more >>

Acta Crystallogr F Struct Biol Commun (Acta crystallographica. Section F, Structural biology communications)
[2021, 77(Pt 5):156-162]

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TSC-insensitive Rheb mutations induce oncogenic transformation through a combination of constitutively active mTORC1 signalling and proteome remodelling.

Jianling Xie, Stuart P De Poi, Sean J Humphrey, Leanne K Hein, John B Bruning, Wenru Pan, Luke A Selth, Timothy J Sargeant, Christopher G Proud,

The mechanistic target of rapamycin complex 1 (mTORC1) is an important regulator of cellular metabolism that is commonly hyperactivated in cancer. Recent cancer genome screens have identified multiple mutations in Ras-homolog enriched in brain (Rheb), the primary activator of mTORC1 that might act as driver oncogenes by causing hyperactivation of ... Read more >>

Cell Mol Life Sci (Cellular and molecular life sciences : CMLS)
[2021, 78(8):4035-4052]

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A turn-on fluorescent PCNA sensor.

Aimee J Horsfall, Theresa Chav, John B Bruning, Andrew D Abell,

The solvatochromic amino-acids 4-DMNA or 4-DAPA, were separately introduced at position 147, 150 or 151 of a short p21 peptide (141-155) known to bind sliding clamp protein PCNA. The ability of these peptides, 1a-3a and 1b-3b, to act as a turn-on fluorescent sensor for PCNA was then investigated. The 4-DMNA-containing ... Read more >>

Bioorg Med Chem Lett (Bioorganic & medicinal chemistry letters)
[2021, 41:128031]

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An antimony-phosphomolybdate microassay of ATPase activity through the detection of inorganic phosphate.

Jordan L Pederick, John B Bruning,

Colorimetric methods are convenient for the determination of inorganic phosphate. However, the acidic conditions required can complicate measurement of ATPase through non-enzymatic ATP hydrolysis. Here we present an optimized antimony-phosphomolybdate microassay for the simple and rapid detection of ATPase activity, with micromolar sensitivity. The low acidity of the color reagent ... Read more >>

Anal Biochem (Analytical biochemistry)
[2021, 623:114170]

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Derivatization of Protein Crystals with I3C using Random Microseed Matrix Screening.

Jia Quyen Truong, Stephanie Nguyen, John B Bruning, Keith E Shearwin,

Protein structure elucidation using X-ray crystallography requires both high quality diffracting crystals and computational solution of the diffraction phase problem. Novel structures that lack a suitable homology model are often derivatized with heavy atoms to provide experimental phase information. The presented protocol efficiently generates derivatized protein crystals by combining random ... Read more >>

J Vis Exp (Journal of visualized experiments : JoVE)
[2021, (167):]

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Vanishing white matter: Eukaryotic initiation factor 2B model and the impact of missense mutations.

Inna Slynko, Stephanie Nguyen, Eline M C Hamilton, Lisanne E Wisse, Iwan J P de Esch, Chris de Graaf, John B Bruning, Christopher G Proud, Truus E M Abbink, Marjo S van der Knaap,

<h4>Background</h4>Vanishing white matter (VWM) is a leukodystrophy, caused by recessive mutations in eukaryotic initiation factor 2B (eIF2B)-subunit genes (EIF2B1-EIF2B5); 80% are missense mutations. Clinical severity is highly variable, with a strong, unexplained genotype-phenotype correlation.<h4>Materials and methods</h4>With information from a recent natural history study, we severity-graded 97 missense mutations. Using in ... Read more >>

Mol Genet Genomic Med (Molecular genetics & genomic medicine)
[2021, 9(3):e1593]

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Unlocking the PIP-box: A peptide library reveals interactions that drive high-affinity binding to human PCNA.

Aimee J Horsfall, Beth A Vandborg, Wioleta Kowalczyk, Theresa Chav, Denis B Scanlon, Andrew D Abell, John B Bruning,

The human sliding clamp, Proliferating Cell Nuclear Antigen (hPCNA), interacts with over 200 proteins through a conserved binding motif, the PIP-box, to orchestrate DNA replication and repair. It is not clear how changes to the features of a PIP-box modulate protein binding and thus how they fine-tune downstream processes. Here, ... Read more >>

J Biol Chem (The Journal of biological chemistry)
[2021, 296:100773]

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Nucleoside selectivity of Aspergillus fumigatus nucleoside-diphosphate kinase.

Stephanie Nguyen, Blagojce Jovcevski, Tara L Pukala, John B Bruning,

Aspergillus fumigatus infections are rising at a disconcerting rate in tandem with antifungal resistance rates. Efforts to develop novel antifungals have been hindered by the limited knowledge of fundamental biological and structural mechanisms of A. fumigatus propagation. Biosynthesis of NTPs, the building blocks of DNA and RNA, is catalysed by NDK. ... Read more >>

FEBS J (The FEBS journal)
[2021, 288(7):2398-2417]

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A comparison of steroid and lipid binding cytochrome P450s from Mycobacterium marinum and Mycobacterium tuberculosis.

Stella A Child, Amna Ghith, John B Bruning, Stephen G Bell,

The steroid lipid binding cytochrome P450 (CYP) enzymes of Mycobacterium tuberculosis are essential for organism survival through metabolism of cholesterol and its derivatives. The counterparts to these enzymes from Mycobacterium marinum were studied to determine the degree of functional conservation between them. Spectroscopic analyses of substrate and inhibitor binding for ... Read more >>

J Inorg Biochem (Journal of inorganic biochemistry)
[2020, 209:111116]

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Structural insights into the role of the acid-alcohol pair of residues required for dioxygen activation in cytochrome P450 enzymes.

Tom Coleman, Jeanette E Stok, Matthew N Podgorski, John B Bruning, James J De Voss, Stephen G Bell,

The cytochrome P450 heme monooxygenases commonly use an acid-alcohol pair of residues, within the I-helix, to activate iron-bound dioxygen. This work aims to clarify conflicting reports on the importance of the alcohol functionality in this process. Mutants of the P450, CYP199A4 (CYP199A4<sub>D251N</sub> and CYP199A4<sub>T252A</sub>), were prepared, characterised and their crystal ... Read more >>

J Biol Inorg Chem (Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry)
[2020, 25(4):583-596]

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d-Alanine-d-alanine ligase as a model for the activation of ATP-grasp enzymes by monovalent cations.

Jordan L Pederick, Andrew P Thompson, Stephen G Bell, John B Bruning,

The ATP-grasp superfamily of enzymes shares an atypical nucleotide-binding site known as the ATP-grasp fold. These enzymes are involved in many biological pathways in all domains of life. One ATP-grasp enzyme, d-alanine-d-alanine ligase (Ddl), catalyzes ATP-dependent formation of the d-alanyl-d-alanine dipeptide essential for bacterial cell wall biosynthesis and is therefore ... Read more >>

J Biol Chem (The Journal of biological chemistry)
[2020, 295(23):7894-7904]

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Analysis of the mutation dynamics of SARS-CoV-2 reveals the spread history and emergence of RBD mutant with lower ACE2 binding affinity

Yong Jia, Gangxu Shen, Stephanie Nguyen, Yujuan Zhang, Keng-Shiang Huang, Hsing-Ying Ho, Wei-Shio Hor, Chih-Hui Yang, John Bruning, Chengdao Li, Wei-Lung Wang,

<h4>Summary</h4> Monitoring the mutation dynamics of SARS-CoV-2 is critical for the development of effective approaches to contain the pathogen. By analyzing 106 SARS-CoV-2 and 39 SARS genome sequences, we provided direct genetic evidence that SARS-CoV-2 has a much lower mutation rate than SARS. Minimum Evolution phylogeny analysis revealed the putative ... Read more >>

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Biophysical Techniques for Distinguishing Ligand Binding Modes in Cytochrome P450 Monooxygenases.

Matthew N Podgorski, Joshua S Harbort, Tom Coleman, Jeanette E Stok, Jake A Yorke, Luet-Lok Wong, John B Bruning, Paul V Bernhardt, James J De Voss, Jeffrey R Harmer, Stephen G Bell,

The cytochrome P450 superfamily of heme monooxygenases catalyzes important chemical reactions across nature. The changes in the optical spectra of these enzymes, induced by the addition of substrates or inhibitors, are critical for assessing how these molecules bind to the P450, enhancing or inhibiting the catalytic cycle. Here we use ... Read more >>

Biochemistry (Biochemistry)
[2020, 59(9):1038-1050]

Cited: 2 times

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Targeting Unconventional Pathways in Pursuit of Novel Antifungals.

Stephanie Nguyen, Jia Q Truong, John B Bruning,

The impact of invasive fungal infections on human health is a serious, but largely overlooked, public health issue. Commonly affecting the immunocompromised community, fungal infections are predominantly caused by species of <i>Candida, Cryptococcus</i>, and <i>Aspergillus</i>. Treatments are reliant on the aggressive use of pre-existing antifungal drug classes that target the ... Read more >>

Front Mol Biosci (Frontiers in molecular biosciences)
[2020, 7:621366]

Cited: 1 time

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Investigation of the requirements for efficient and selective cytochrome P450 monooxygenase catalysis across different reactions.

Matthew N Podgorski, Tom Coleman, Rebecca R Chao, James J De Voss, John B Bruning, Stephen G Bell,

The cytochrome P450 metalloenzyme (CYP) CYP199A4 from Rhodopseudomonas palustris HaA2 catalyzes the highly efficient oxidation of para-substituted benzoic acids. Here we determined crystal structures of CYP199A4, and the binding and turnover parameters, with different meta-substituted benzoic acids in order to establish which criteria are important for efficient catalysis. When compared ... Read more >>

J Inorg Biochem (Journal of inorganic biochemistry)
[2020, 203:110913]

Cited: 1 time

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Targeting PCNA with Peptide Mimetics for Therapeutic Purposes.

Aimee J Horsfall, Andrew D Abell, John B Bruning,

Proliferating cell nuclear antigen (PCNA) is an excellent inhibition target to shut down highly proliferative cells and thereby develop a broad-spectrum cancer therapeutic. It interacts with a wide variety of proteins through a conserved motif referred to as the PCNA-interacting protein (PIP) box. There is large sequence diversity between high-affinity ... Read more >>

Chembiochem (Chembiochem : a European journal of chemical biology)
[2020, 21(4):442-450]

Cited: 4 times

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An aldo-keto reductase with 2-keto-l-gulonate reductase activity functions in l-tartaric acid biosynthesis from vitamin C in Vitis vinifera.

Yong Jia, Crista A Burbidge, Crystal Sweetman, Emi Schutz, Kathy Soole, Colin Jenkins, Robert D Hancock, John B Bruning, Christopher M Ford,

Tartaric acid has high economic value as an antioxidant and flavorant in food and wine industries. l-Tartaric acid biosynthesis in wine grape (<i>Vitis vinifera</i>) uses ascorbic acid (vitamin C) as precursor, representing an unusual metabolic fate for ascorbic acid degradation. Reduction of the ascorbate breakdown product 2-keto-l-gulonic acid to l-idonic ... Read more >>

J Biol Chem (The Journal of biological chemistry)
[2019, 294(44):15932-15946]

Cited: 4 times

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