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1. The Multifunctional Protein in Peroxisomal β-Oxidation

Author

Caspar Christensen, Valerie E. Pye, Anette Henriksen, Allan Nørgaard, and Susan Arent

Subjects
biology, Catabolism, food and beverages, Dehydrogenase, Cell Biology, Fatty acid degradation, Peroxisome, biology.organism_classification, Biochemistry, Isozyme, chemistry.chemical_compound, chemistry, Arabidopsis, Arabidopsis thaliana, Plant hormone, Molecular Biology
Abstract

Plant fatty acids can be completely degraded within the peroxisomes. Fatty acid degradation plays a role in several plant processes including plant hormone synthesis and seed germination. Two multifunctional peroxisomal isozymes, MFP2 and AIM1, both with 2-trans-enoyl-CoA hydratase and l-3-hydroxyacyl-CoA dehydrogenase activities, function in mouse ear cress (Arabidopsis thaliana) peroxisomal β-oxidation, where fatty acids are degraded by the sequential removal of two carbon units. A deficiency in either of the two isozymes gives rise to a different phenotype; the biochemical and molecular background for these differences is not known. Structure determination of Arabidopsis MFP2 revealed that plant peroxisomal MFPs can be grouped into two families, as defined by a specific pattern of amino acid residues in the flexible loop of the acyl-binding pocket of the 2-trans-enoyl-CoA hydratase domain. This could explain the differences in substrate preferences and specific biological functions of the two isozymes. The in vitro substrate preference profiles illustrate that the Arabidopsis AIM1 hydratase has a preference for short chain acyl-CoAs compared with the Arabidopsis MFP2 hydratase. Remarkably, neither of the two was able to catabolize enoyl-CoA substrates longer than 14 carbon atoms efficiently, suggesting the existence of an uncharacterized long chain enoyl-CoA hydratase in Arabidopsis peroxisomes.

Published
2010

2. Structure and function of plant acyl-CoA oxidases

Author

Valerie E. Pye, Susan Arent, and Anette Henriksen

Subjects
Physiology, Molecular Sequence Data, Plant Science, Mitochondrion, Protein Structure, Secondary, Substrate Specificity, Structure-Activity Relationship, Acyl-CoA, chemistry.chemical_compound, Acyl-CoA Dehydrogenases, Biosynthesis, Genetics, Acyl-CoA oxidase, Amino Acid Sequence, Plant Proteins, chemistry.chemical_classification, biology, Fatty acid, Acyl CoA dehydrogenase, Peroxisome, biology.organism_classification, chemistry, Biochemistry, biology.protein, Acyl-CoA Oxidase, Plant hormone
Abstract

Acyl-CoA oxidases (in peroxisomes) and acyl-CoA dehydrogenases (in mitochondria) catalyse the first step in fatty acid beta-oxidation, the pathway responsible for lipid catabolism and plant hormone biosynthesis. The interplay and differences between peroxisomal and mitochondrial beta-oxidation processes are highlighted by the variation in the enzymes involved. Structure and sequence comparisons are made with a focus on the enzyme's mechanistic means to control electron transfer paths, reactivity towards molecular oxygen, and spatial and architectural requirements for substrate discrimination.

Published
2008

3. Controlling Electron Transfer in Acyl-CoA Oxidases and Dehydrogenases

Author

Jenny Mackenzie, Anette Henriksen, Susan Arent, and Lise Pedersen

Subjects
Flavin adenine dinucleotide, chemistry.chemical_classification, Oxidase test, Substrate Interaction, biology, Active site, Dehydrogenase, Cell Biology, Peroxisome, Biochemistry, chemistry.chemical_compound, chemistry, Acyl binding, Oxidoreductase, biology.protein, lipids (amino acids, peptides, and proteins), Molecular Biology
Abstract

Plants produce a unique peroxisomal short chain-specific acyl-CoA oxidase (ACX4) for β-oxidation of lipids. The short chain-specific oxidase has little resemblance to other peroxisomal acyl-CoA oxidases but has an ∼30% sequence identity to mitochondrial acyl-CoA dehydrogenases. Two biochemical features have been linked to structural properties by comparing the structures of short chain-specific Arabidopsis thaliana ACX4 with and without a substrate analogue bound in the active site to known acyl-CoA oxidases and dehydrogenase structures: (i) a solvent-accessible acyl binding pocket is not required for oxygen reactivity, and (ii) the oligomeric state plays a role in substrate pocket architecture but is not linked to oxygen reactivity. The structures indicate that the acyl-CoA oxidases may encapsulate the electrons for transfer to molecular oxygen by blocking the dehydrogenase substrate interaction site with structural extensions. A small binding pocket observed adjoining the flavin adenine dinucleotide N5 and C4a atoms could increase the number of productive encounters between flavin adenine dinucleotide and O2.

Published
2006

4. Allosteric properties of the GTP activated and CTP inhibited uracil phosphoribosyltransferase from the thermoacidophilic archaeon Sulfolobus solfataricus

Author

Kaj Frank Jensen, Sine Larsen, Lise Schack, and Susan Arent

Subjects
chemistry.chemical_classification, Uracil phosphoribosyltransferase, biology, GTP', ved/biology, Sulfolobus solfataricus, ved/biology.organism_classification_rank.species, Allosteric regulation, Uracil, Cell Biology, Biochemistry, Enzyme assay, enzymes and coenzymes (carbohydrates), chemistry.chemical_compound, Enzyme, chemistry, biology.protein, heterocyclic compounds, Enzyme kinetics, Molecular Biology
Abstract

The upp gene, encoding uracil phosphoribosyltransferase (UPRTase) from the thermoacidophilic archaeon Sulfolobus solfataricus, was cloned and expressed in Escherichia coli. The enzyme was purified to homogeneity. It behaved as a tetramer in solution and showed optimal activity at pH 5.5 when assayed at 60 °C. Enzyme activity was strongly stimulated by GTP and inhibited by CTP. GTP caused an approximately 20-fold increase in the turnover number kcat and raised the Km values for 5-phosphoribosyl-1-diphosphate (PRPP) and uracil by two- and >10-fold, respectively. The inhibition by CTP was complex as it depended on the presence of the reaction product UMP. Neither CTP nor UMP were strong inhibitors of the enzyme, but when present in combination their inhibition was extremely powerful. Ligand binding analyses showed that GTP and PRPP bind cooperatively to the enzyme and that the inhibitors CTP and UMP can be bound simultaneously (KD equal to 2 and 0.5 µm, respectively). The binding of each of the inhibitors was incompatible with binding of PRPP or GTP. The data indicate that UPRTase undergoes a transition from a weakly active or inactive T-state, favored by binding of UMP and CTP, to an active R-state, favored by binding of GTP and PRPP.

Published
2005

5. Allosteric Regulation and Communication between Subunits in Uracil Phosphoribosyltransferase from Sulfolobus solfataricus

Author

Pernille Harris, Susan Arent, Kaj Frank Jensen, and Sine Larsen

Subjects
Models, Molecular, Uracil phosphoribosyltransferase, Sequence Homology, Amino Acid, Stereochemistry, ved/biology, Molecular Sequence Data, Allosteric regulation, Sulfolobus solfataricus, ved/biology.organism_classification_rank.species, Uracil, Biochemistry, Catalysis, Recombinant Proteins, Uridine, chemistry.chemical_compound, Allosteric Regulation, chemistry, Tetramer, Transferase, CTP binding, Amino Acid Sequence, Pentosyltransferases, Crystallization
Abstract

Uracil phosphoribosyltransferase (UPRTase) catalyzes the conversion of 5-phosphate-alpha-1-diphosphate (PRPP) and uracil to uridine 5'-monophosphate (UMP) and diphosphate. The UPRTase from Sulfolobus solfataricus has a unique regulation by nucleoside triphosphates compared to UPRTases from other organisms. To understand the allosteric regulation, crystal structures were determined for S. solfataricus UPRTase in complex with UMP and with UMP and the allosteric inhibitor CTP. Also, a structure with UMP bound in half of the active sites was determined. All three complexes form tetramers but reveal differences in the subunits and their relative arrangement. In the UPRTase-UMP complex, the peptide bond between a conserved arginine residue (Arg80) and the preceding residue (Leu79) adopts a cis conformation in half of the subunits and a trans conformation in the other half and the tetramer comprises two cis-trans dimers. In contrast, four identical subunits compose the UPRTase-UMP-CTP tetramer. CTP binding affects the conformation of Arg80, and the Arg80 conformation in the UPRTase-UMP-CTP complex leaves no room for binding of the substrate PRPP. The different conformations of Arg80 coupled to rearrangements in the quaternary structure imply that this residue plays a major role in regulation of the enzyme and in communication between subunits. The ribose ring of UMP adopts alternative conformations in the cis and trans subunits of the UPRTase-UMP tetramer with associated differences in the interactions of the catalytically important Asp209. The active-site differences have been related to proposed kinetic models and provide an explanation for the regulatory significance of the C-terminal Gly216.

Published
2004

6. A cross-sectional study of traditional Chinese medicine practitioner’s knowledge, treatment strategies and integration of practice of chronic pelvic pain in women

Author

Susan Arentz, Caroline Smith, Rebecca Redmond, Jason Abbott, and Mike Armour

Subjects
Persistent pelvic pain, Vaginismus, Dysmenorrhea, Vulvodynia, Endometriosis, Dyspareunia, Other systems of medicine, RZ201-999
Abstract

Abstract Background Chronic pelvic pain (CPP) in women is persistent, intermittent cyclical and non-cyclical lower abdominal pain, lasting for more than 6 months. Traditional Chinese Medicine (TCM) is a popular treatment option for women’s health conditions, but little is known about how treatment for CPP is delivered by TCM practitioners. The aim of this survey was to explore practitioners understanding and treatment of women with CPP, and how they integrate their management and care into the health care system. Method An online cross-sectional survey of registered TCM practitioners in Australia and New Zealand between May and October 2018. Survey domains included treatment characteristics (e.g. frequency), evaluation of treatment efficacy, referral networks, and sources of information that informed clinical decision making. Results One hundred and twenty-two registered TCM practitioners responded to this survey, 91.7% reported regular treatment of women with CPP. Treatment decisions were most-often guided by a combination of biomedical and TCM diagnosis (77.6%), and once per week was the most common treatment frequency (66.7%) for acupuncture. Meditation (63.7%) and dietary changes (57.8%) were other commonly used approaches to management. The effectiveness of treatment was assessed using multiple approaches, most commonly pain scales, (such as the numeric rating scale) and any change in use of analgesic medications. Limitations to TCM treatment were reported by over three quarters (83.7%) of practitioners, most commonly due to cost (56.5%) and inconvenience (40.2%) rather than safety or lack of efficacy. Sources informing practice were most often Integration within the wider healthcare system was common with over two thirds (67.9%) receiving referrals from health care providers. Conclusion TCM practitioners seeing women with various CPP symptoms, commonly incorporate both traditional and modern diagnostic methods to inform their treatment plan, monitor treatment progress using commonly accepted approaches and measures and often as a part of multidisciplinary healthcare for women with CPP.

Published
2021
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7. The multifunctional protein in peroxisomal beta-oxidation: structure and substrate specificity of the Arabidopsis thaliana protein MFP2

Author

Susan, Arent, Caspar E, Christensen, Valerie E, Pye, Allan, Nørgaard, and Anette, Henriksen

Subjects
Arabidopsis Proteins, Protein Conformation, Fatty Acids, Arabidopsis, food and beverages, Crystallography, X-Ray, Models, Biological, Protein Structure, Tertiary, Substrate Specificity, Oxygen, Phenotype, Gene Expression Regulation, Plant, Protein Structure and Folding, Peroxisomes, Protein Isoforms, Oxidation-Reduction, Protein Binding
Abstract

Plant fatty acids can be completely degraded within the peroxisomes. Fatty acid degradation plays a role in several plant processes including plant hormone synthesis and seed germination. Two multifunctional peroxisomal isozymes, MFP2 and AIM1, both with 2-trans-enoyl-CoA hydratase and l-3-hydroxyacyl-CoA dehydrogenase activities, function in mouse ear cress (Arabidopsis thaliana) peroxisomal beta-oxidation, where fatty acids are degraded by the sequential removal of two carbon units. A deficiency in either of the two isozymes gives rise to a different phenotype; the biochemical and molecular background for these differences is not known. Structure determination of Arabidopsis MFP2 revealed that plant peroxisomal MFPs can be grouped into two families, as defined by a specific pattern of amino acid residues in the flexible loop of the acyl-binding pocket of the 2-trans-enoyl-CoA hydratase domain. This could explain the differences in substrate preferences and specific biological functions of the two isozymes. The in vitro substrate preference profiles illustrate that the Arabidopsis AIM1 hydratase has a preference for short chain acyl-CoAs compared with the Arabidopsis MFP2 hydratase. Remarkably, neither of the two was able to catabolize enoyl-CoA substrates longer than 14 carbon atoms efficiently, suggesting the existence of an uncharacterized long chain enoyl-CoA hydratase in Arabidopsis peroxisomes.

Published
2010

8. Peroxisomal plant 3-ketoacyl-CoA thiolase structure and activity are regulated by a sensitive redox switch

Author

Valerie E. Pye, Caspar Christensen, Anette Henriksen, Susan Arent, and James H. Dyer

Subjects
Substrate channeling, Arabidopsis, Crystallography, X-Ray, Biochemistry, Models, Biological, Gene Expression Regulation, Enzymologic, Substrate Specificity, chemistry.chemical_compound, Gene Expression Regulation, Plant, Peroxisomes, Transferase, Cloning, Molecular, Molecular Biology, Beta oxidation, chemistry.chemical_classification, Fatty acid metabolism, biology, Thiolase, Fatty Acids, Fatty acid, Active site, Cell Biology, Peroxisome, Acetyl-CoA C-Acyltransferase, Lipids, Oxygen, chemistry, Protein Structure and Folding, biology.protein, Helianthus, Dimerization, Oxidation-Reduction
Abstract

The breakdown of fatty acids, performed by the beta-oxidation cycle, is crucial for plant germination and sustainability. beta-Oxidation involves four enzymatic reactions. The final step, in which a two-carbon unit is cleaved from the fatty acid, is performed by a 3-ketoacyl-CoA thiolase (KAT). The shortened fatty acid may then pass through the cycle again (until reaching acetoacetyl-CoA) or be directed to a different cellular function. Crystal structures of KAT from Arabidopsis thaliana and Helianthus annuus have been solved to 1.5 and 1.8 A resolution, respectively. Their dimeric structures are very similar and exhibit a typical thiolase-like fold; dimer formation and active site conformation appear in an open, active, reduced state. Using an interdisciplinary approach, we confirmed the potential of plant KATs to be regulated by the redox environment in the peroxisome within a physiological range. In addition, co-immunoprecipitation studies suggest an interaction between KAT and the multifunctional protein that is responsible for the preceding two steps in beta-oxidation, which would allow a route for substrate channeling. We suggest a model for this complex based on the bacterial system.

Published
2010

9. The effectiveness of a modified Gui Zhi Fu Ling Wan formulation (Gynoclear™) for the treatment of endometriosis: a study protocol for a placebo-controlled, double-blind, randomised controlled trial

Author

Mike Armour, Mahmoud A. Al-Dabbas, Carolyn Ee, Caroline A. Smith, Jane Ussher, Susan Arentz, Kenny Lawson, and Jason Abbott

Subjects
Endometriosis, Gynoclear, Chinese herbal medicine, Pelvic pain, Medicine (General), R5-920
Abstract

Abstract Background Endometriosis is the presence of tissue similar to that of the endometrium outside the uterine cavity and is the most common cause of chronic pelvic pain. Current non-surgical treatments such as non-steroidal anti-inflammatories, oral contraceptive pills and hormonal treatments have limited effectiveness, and the side effect profile is bothersome. This study will evaluate the efficacy of Gynoclear™ by change in endometriosis-related pain based on the Endometriosis Pain Daily Diary (EPPD) scores. Methods This randomised, double-blind, placebo-controlled trial will recruit a minimum of 90 adult participants across Australia who have a laparoscopic visualisation/confirmation of endometriosis in the last 5 years and have current moderate or greater pelvic pain. Participants will be randomly allocated in a 1:1 ratio to receive either Gynoclear™ (active) or placebo. Gyncolear’s active ingredients are Carthamus tinctorius (Safflower), Cinnamomum cassia (Chinese cinnamon), Poria cocos (Hoelen), Paeonia suffriticosa (Tree peony), Paeonia lactiflora (Peony) and Salvia miltiorrhiza (Red sage). Participants are asked to complete a total of 5 months’ worth of pain diary entries via the EPDD v3, including 1-month screening, 2-month treatment period and 1-month post-treatment follow-up. The primary outcome variable is change in endometriosis-related pain based on the EPDD v3 scores. Secondary outcomes include change in health-related quality of life via the Endometriosis Health Profile (EHP-30), SF-12 and EQ-5D scores as well as changes in rescue analgesic usage, dyspareunia and fatigue via the EPDD. Discussion This study will determine the safety and efficacy of Gynoclear™ to reduce the severity and duration of non-cyclical pelvic pain, dysmenorrhoea, dyspareunia and other symptoms of endometriosis. Study outcomes will be of interest to health professionals and members of the public who suffer from endometriosis. Trial registration Australia and New Zealand Clinical Trials Registry ACTRN12619000807156 . Registered on 3 June 2019.

Published
2021
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10. Perceptions and experiences of lifestyle interventions in women with polycystic ovary syndrome (PCOS), as a management strategy for symptoms of PCOS

Author

Susan Arentz, Caroline A. Smith, Jason Abbott, and Alan Bensoussan

Subjects
Polycystic ovary syndrome, Healthy lifestyle, Exercise, Women’s health, Gynecology and obstetrics, RG1-991, Public aspects of medicine, RA1-1270
Abstract

Abstract Background The international clinical practice guidelines for PCOS emphasize diet and exercise as first-line management of clinical signs and symptoms. This study aimed to describe the patterns, perceptions and experiences of lifestyle interventions for women in the community with PCOS. Method An electronic survey of 493 members of two PCOS consumer support groups, collected by cloud-based Survey Monkey, described women’s types and patterns of diet and exercise, experiences and perceptions of effectiveness. Women were recruited from the Polycystic Ovary Association of Australia (POSAA) and from the Facebook group, PCOS University Research Group. Associations between participants perceptions of effectiveness, and diet types and exercise patterns were assessed using logistic regression. Response bias for the POSAA group was assessed with a continuum of resistance model. Results 91% of POSAA members and 311 Facebook group members aged 16–50 years responded to the survey. Nearly all women reported adjusting their dietary and exercise practices with the aim to improve their health and/or PCOS (82% and 73% respectively), however less than 13% reported achievement of health goals (12.2% and 8.1% respectively). Low carbohydrate, high protein diets, and vigorous activity were associated with self-perceived effectiveness (r.0.16, p

Published
2021
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11. Interaction of benzoate pyrimidine analogues with class 1A dihydroorotate dehydrogenase from Lactococcus lactis

Author

Susan Arent, Eva Johansson, Abigail E. Wolfe, Majbritt Thymark, Samuel G. Gattis, Yu Chen Hu, Rebecca L. Fagan, Bruce A. Palfey, and Sine Larsen

Subjects
Models, Molecular, Oxidoreductases Acting on CH-CH Group Donors, Stereochemistry, Dihydroorotate Dehydrogenase, Flavin group, Calorimetry, Biochemistry, Oxidoreductase, Hydroxybenzoates, chemistry.chemical_classification, Binding Sites, biology, Hydrogen bond, Lactococcus lactis, Isothermal titration calorimetry, Hydrogen Bonding, Resorcinols, Hydrogen-Ion Concentration, biology.organism_classification, Kinetics, chemistry, Amino Acid Substitution, Pyrimidine metabolism, Dihydroorotate dehydrogenase, Titration
Abstract

Dihydroorotate dehydrogenases (DHODs) catalyze the oxidation of dihydroorotate to orotate in the only redox reaction in pyrimidine biosynthesis. The pyrimidine binding sites are very similar in all structurally characterized DHODs, suggesting that the prospects for identifying a class-specific inhibitor directed against this site are poor. Nonetheless, two compounds that bind specifically to the Class 1A DHOD from Lactococcus lactis, 3,4-dihydroxybenzoate (3,4-diOHB) and 3,5-dihydroxybenzoate (3,5-diOHB), have been identified [Palfey et al. (2001) J. Med. Chem. 44, 2861-2864]. The mechanism of inhibitor binding to the Class 1A DHOD from L. lactis has now been studied in detail and is reported here. Titrations showed that 3,4-diOHB binds more tightly at higher pH, whereas the opposite is true for 3,5-diOHB. Isothermal titration calorimetry and absorbance spectroscopy showed that 3,4-diOHB ionizes to the phenolate upon binding to the enzyme, but 3,5-diOHB does not. The charge-transfer band that forms in the 3,4-diOHB complex allowed the kinetics of binding to be observed in stopped-flow experiments. Binding was slow enough to observe from pH 6 to pH 8 and was (minimally) a two-step process consisting of the rapid formation of a complex that isomerized to the final charge-transfer complex. Orotate and 3,5-diOHB bind too quickly to follow directly, but their dissociation kinetics were studied by competition and described adequately with a single step. Crystal structures of both inhibitor complexes were determined, showing that 3,5-diOHB binds in the same orientation as orotate. In contrast, 3,4-diOHB binds in a twisted orientation, enabling one of its phenolic oxygens to form a very strong hydrogen bond to an asparagine, thus stabilizing the phenolate and causing charge-transfer interactions with the pi-system of the flavin, resulting in a green color.

Published
2007

12. The extraordinary specificity of xanthine phosphoribosyltransferase from Bacillus subtilis elucidated by reaction kinetics, ligand binding, and crystallography

Author

Kaj Frank Jensen, Jan Neuhard, Anders Kadziola, Susan Arent, and Sine Larsen

Subjects
Models, Molecular, Stereochemistry, Guanine, Molecular Sequence Data, Repressor, Bacillus subtilis, Ligands, Biochemistry, chemistry.chemical_compound, Transferase, Amino Acid Sequence, Pentosyltransferases, Hypoxanthine, DNA Primers, Purr, Crystallography, biology, Base Sequence, Sequence Homology, Amino Acid, Chemistry, Hydrogen Bonding, Hydrogen-Ion Concentration, biology.organism_classification, Xanthine, Xanthine phosphoribosyltransferase, Kinetics
Abstract

Xanthine phosphoribosyltransferase (XPRTase) from Bacillus subtilis is a representative of the highly xanthine specific XPRTases found in Gram-positive bacteria. These XPRTases constitute a distinct subclass of 6-oxopurine PRTases, which deviate strongly from the major class of H(X)GPRTases with respect to sequence, PRPP binding motif, and oligomeric structure. They are more related with the PurR repressor of Gram-positive bacteria, the adenine PRTase, and orotate PRTase. The catalytic function and high specificity for xanthine of B. subtilis XPRTase were investigated by ligand binding studies and reaction kinetics as a function of pH with xanthine, hypoxanthine, and guanine as substrates. The crystal structure of the dimeric XPRTase-GMP complex was determined to 2.05 A resolution. In a sequential reaction mechanism XPRTase binds first PRPP, stabilizing its active dimeric form, and subsequently xanthine. The XPRTase is able also to react with guanine and hypoxanthine albeit at much lower (10(-)(4)-fold) catalytic efficiency. Different pK(a) values for the bases and variations in their electrostatic potential can account for these catalytic differences. The unique base specificity of XPRTase has been related to a few key residues in the active site. Asn27 can in different orientations form hydrogen bonds to an amino group or an oxo group at the 2-position of the purine base, and Lys156 is positioned to make a hydrogen bond with N7. This and the absence of a catalytic carboxylate group near the N7-position require the purine base to dissociate a proton spontaneously in order to undergo catalysis.

Published
2006

13. LNA guanine and 2,6-diaminopurine. Synthesis, characterization and hybridization properties of LNA 2,6-diaminopurine containing oligonucleotides

Author

Daniel Sejer Pedersen, Susan Arent, Christoph Rosenbohm, Miriam Frieden, Flemming Reissig Jensen, Troels Koch, and Sine Larsen

Subjects
Spectrometry, Mass, Electrospray Ionization, Guanine, Magnetic Resonance Spectroscopy, Oligonucleotide, Stereochemistry, 2,6-Diaminopurine, Organic Chemistry, Clinical Biochemistry, Oligonucleotides, Pharmaceutical Science, RNA, Nucleic Acid Hybridization, Nuclear magnetic resonance spectroscopy, Biochemistry, Nucleic acid thermodynamics, chemistry.chemical_compound, chemistry, Drug Discovery, Molecular Medicine, 2-Aminopurine, Molecular Biology, DNA, Cytosine
Abstract

LNA guanine and 2,6-diaminopurine (D) phosphoramidites have been synthesized as building blocks for antisense oligonucleotides (ON). The effects of incorporating LNA D into ON were investigated. As expected, LNA D containing ON showed increased affinity towards complementary DNA (Delta Tm +1.6 to +3.0 degrees C) and RNA (Delta Tm +2.6 to +4.6 degrees C) ON. To evaluate if LNA D containing ON have an enhanced mismatch sensitivity compared to their complementary LNA A containing ON thermal denaturation experiments towards singly mismatched DNA and RNA ON were undertaken. Replacing one LNA A residue with LNA D, in fully LNA modified ON, resulted in higher mismatch sensitivity towards DNA ON (Delta Delta Tm -4 to >-17 degrees C). The same trend was observed towards singly mismatched RNA ON (Delta Delta Tm D-a = -8.7 degrees C and D-g = -4.5 degrees C) however, the effect was less clearcut and LNA A showed a better mismatch sensitivity than LNA D towards cytosine (Delta Tm +5.5 degrees C).

Published
2003

14. Lactococcus lactis dihydroorotate dehydrogenase A mutants reveal important facets of the enzymatic function

Author

Leila Lo Leggio, Kaj Frank Jensen, Susan Arent, Sine Larsen, M. Ottosen, Sofie Nørager, and Olof Björnberg

Subjects
Models, Molecular, Oxidoreductases Acting on CH-CH Group Donors, Stereochemistry, Protein Conformation, Dimer, Mutant, Dihydroorotate Dehydrogenase, Biochemistry, Polymerase Chain Reaction, chemistry.chemical_compound, Structure-Activity Relationship, Oxidoreductase, Electrochemistry, Binding site, Molecular Biology, chemistry.chemical_classification, Orotic Acid, Binding Sites, biology, Molecular Structure, Lactococcus lactis, Mutagenesis, Active site, Hydrogen Bonding, Cell Biology, biology.organism_classification, Kinetics, chemistry, Spectrophotometry, biology.protein, Dihydroorotate dehydrogenase, Crystallization, Oxidoreductases, Oxidation-Reduction, Mathematics
Abstract

Dihydroorotate dehydrogenases (DHODs) are flavoenzymes catalyzing the oxidation of (S)-dihydroorotate to orotate in the biosynthesis of UMP, the precursor of all other pyrimidine nucleotides. On the basis of sequence, DHODs can be divided into two classes, class 1, further divided in subclasses 1A and 1B, and class 2. This division corresponds to differences in cellular location and the nature of the electron acceptor. Herein we report a study of Lactococcus lactis DHODA, a representative of the class 1A enzymes. Based on the DHODA structure we selected seven residues that are highly conserved between both main classes of DHODs as well as three residues representing surface charges close to the active site for site-directed mutagenesis. The availability of both kinetic and structural data on the mutant enzymes allowed us to define the roles individual structural segments play in catalysis. We have also structurally proven the presence of an open active site loop in DHODA and obtained information about the interactions that control movements of loops around the active site. Furthermore, in one mutant structure we observed differences between the two monomers of the dimer, confirming an apparent asymmetry between the two substrate binding sites that was indicated by the kinetic results.

Published
2003

15. Zinc for the prevention or treatment of acute viral respiratory tract infections in adults: a rapid systematic review and meta-analysis of randomised controlled trials

Author

Stephen Leeder, Dominik Mertz, Jennifer Beardsley, Guoyan Yang, Jennifer Hunter, Susan Arentz, Joshua Goldenberg, and Stephen P Myers

Subjects
Medicine
Abstract

Objective To evaluate the benefits and risks of zinc formulations compared with controls for prevention or treatment of acute viral respiratory tract infections (RTIs) in adults.Method Seventeen English and Chinese databases were searched in April/May 2020 for randomised controlled trials (RCTs), and from April/May 2020 to August 2020 for SARS-CoV-2 RCTs. Cochrane rapid review methods were applied. Quality appraisals used the Risk of Bias 2.0 and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.Results Twenty-eight RCTs with 5446 participants were identified. None were specific to SARS-CoV-2. Compared with placebo, oral or intranasal zinc prevented 5 RTIs per 100 person-months (95% CI 1 to 8, numbers needed to treat (NNT)=20, moderate-certainty/quality). Sublingual zinc did not prevent clinical colds following human rhinovirus inoculations (relative risk, RR 0.96, 95% CI 0.77 to 1.21, moderate-certainty/quality). On average, symptoms resolved 2 days earlier with sublingual or intranasal zinc compared with placebo (95% CI 0.61 to 3.50, very low-certainty/quality) and 19 more adults per 100 were likely to remain symptomatic on day 7 without zinc (95% CI 2 to 38, NNT=5, low-certainty/quality). There were clinically significant reductions in day 3 symptom severity scores (mean difference, MD −1.20 points, 95% CI −0.66 to −1.74, low-certainty/quality), but not average daily symptom severity scores (standardised MD −0.15, 95% CI −0.43 to 0.13, low-certainty/quality). Non-serious adverse events (AEs) (eg, nausea, mouth/nasal irritation) were higher (RR 1.41, 95% CI 1.17 to 1.69, NNHarm=7, moderate-certainty/quality). Compared with active controls, there were no differences in illness duration or AEs (low-certainty/quality). No serious AEs were reported in the 25 RCTs that monitored them (low-certainty/quality).Conclusions In adult populations unlikely to be zinc deficient, there was some evidence suggesting zinc might prevent RTIs symptoms and shorten duration. Non-serious AEs may limit tolerability for some. The comparative efficacy/effectiveness of different zinc formulations and doses were unclear. The GRADE-certainty/quality of the evidence was limited by a high risk of bias, small sample sizes and/or heterogeneity. Further research, including SARS-CoV-2 clinical trials is warranted.PROSPERO registration number CRD42020182044.

Published
2021
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16. The Health Needs, Treatment Options, and Experiences from Treatment Including Complementary Medicine of Women with Diminished Ovarian Reserve

Author

Alison MAUNDER, Susan ARENTZ, Mike ARMOUR, and Carolyn EE

Subjects
Reproduction, QH471-489
Abstract

Background: Women with diminished ovarian reserve (DOR) have fewer oocytes than would be expected at their age. While a decrease in ovarian reserve is a normal part of ageing, some women experience a decrease beyond what is physiologically expected due to normal age-related decline. Optimal management of women with DOR remains unclear, with medically assisted reproduction (MAR) being the only option being offered to women with DOR trying to conceive with autologous oocytes. The success rate of MAR, however, is significantly lower in women with DOR than those with a normal ovarian reserve. There is no data from a representative sample as to the needs, treatment options and experiences of women with DOR in Australia. Many women in Australia use complementary medicine to improve their chances of having a live healthy baby, with women attempting to conceive being more likely to consult a naturopath than women who are not trying to conceive. We do not know, however, if women with DOR are using complementary medicine, why they are using it and whether they have found the treatment to be helpful. Aim: To determine the health needs of women with DOR, their experiences and treatment decisions including their reasons for choosing any potential complementary medicine options including naturopathy. Method: This is a cross-sectional survey of women aged 18 years or over who have been diagnosed with diminished ovarian reserve and are living in Australia or New Zealand. Participants are recruited through health websites, newsletters and social media. Each participant completes an anonymous online survey asking about their diagnosis, fertility aspirations, treatments recommended and undertaken, use and experience of traditional, integrative and complementary medicine. Results: Ethics approval was gained for the survey in March 2021. Data collection began in April 2021 and is due to be completed by the end of June 2021. An estimate of 150 participants will be recruited. Results will be analysed and available for presentation at the FSA conference in September 2021. Conclusion: This body of research will contribute to the understanding of the health needs and treatment options for women with DOR, highlight the potential strengths and limitations of complementary medicine for managing DOR and guide future research priorities.

Published
2022
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20. Honeybee products for the treatment and recovery from viral respiratory infections including SARS-CoV-2: A rapid systematic review

Author

Susan Arentz, Jennifer Hunter, Baljit Khamba, Michelle Mravunac, Zemirah Lee, Kristen Alexander, Romy Lauche, Joshua Goldenberg, and Stephen P Myers

Subjects
Long-COVID, COVID-19, Coronavirus pandemic, TCIM, Complementary medicine, Miscellaneous systems and treatments, RZ409.7-999
Abstract

Background: This rapid review systematically evaluated the effects of honeybee products compared to controls for the prevention, duration, severity, and recovery of acute viral respiratory tract infections (RTIs), including SARS-CoV-2, in adults and children. Methods: Cochrane rapid review methods were applied. Four English databases plus preprint servers and trial registries were searched for randomized controlled trials (RCTs). The evidence was appraised and synthesized using RoB 2.0 and GRADE. Results: 27 results were derived from 9 RCTs that included 674 adults and 781 children. In hospitalized adults with SARS-CoV-2, propolis plus usual-care compared to usual-care alone reduced the risk of shock, respiratory failure and kidney injury and duration of hospital admission. Honey was less effective than Guaifenesin for reducing cough severity at 60-minutes in adults with non-specific acute viral RTIs. Compared to coffee, honey plus coffee, and honey alone reduced the severity of post-infectious cough in adults. Honey reduced the duration of cough in children compared to placebo and salbutamol; and the global impact of nocturnal cough after one night compared to usual-care alone and pharmaceutical cough medicines. Conclusion: More studies are needed to robustly assess honeybee's role in SARS-CoV-2 and non-specific viral respiratory infections. Protocol registration: PROSPERO: CRD42020193847.

Published
2021
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21. Choose your shortcuts wisely: COVID-19 rapid reviews of traditional, complementary and integrative medicine

Author

Jennifer Hunter, Susan Arentz, Joshua Goldenberg, Guoyan Yang, Jennifer Beardsley, Myeong Soo Lee, and Stephen P. Myers

Subjects
SARS-CoV-2, Rapid review, Systematic review, Evidence synthesis, Methodology, Miscellaneous systems and treatments, RZ409.7-999
Abstract

Background: The COVID-19 pandemic has led to an explosion of rapid reviews geared towards providing time sensitive answers for clinical and policy decision-makers. Rapid reviews (RRs) strike a balance between rigour and rapidity to minimise bias and optimise transparency within specified constraints. Methods: This review article appraised the methods and reporting standards of a convenience sample of RR protocols and RRs of COVID-19 clinical management questions, published in the first six-months of 2020. Inclusion criteria were all RR protocols evaluating traditional, complementary, and integrative medicine (TCIM) registered on PROSPERO, and all RRs indexed on PubMed or published on the Oxford COVID-19 Evidence Service. A purpose-specific 9-item reporting checklist reflecting recommended minimum requirements for RRs was applied. Findings were synthesised and narrated in the context of methodological considerations for conducting and reporting RRs of TCIM. Results: Included studies were five RR protocols of TCIM and 16 RRs, of which five considered TCIM. Wide variations in RR methods were proposed or applied, as were the reporting standards. All five RRs that evaluated TCIM had the lowest reporting standards that limited reproducibility and transparency. Despite accepted recommendations, most RRs did not publish a protocol. Conclusions: We propose that specific research disciplines, such as TCIM, have a uniqueness that may lead to unacceptable outputs if minimum methodological standards are not applied. The recommended minimum requirements will optimise the credibility of rapid reviews of TCIM and limit the risk of prematurely disregarding a potentially effective intervention.

Published
2020
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22. Rapid review protocol: Zinc for the prevention or treatment of COVID-19 and other coronavirus-related respiratory tract infections

Author

Jennifer Hunter, Susan Arentz, Joshua Goldenberg, Guoyan Yang, Jennifer Beardsley, Dominik Mertz, and Stephen Leeder

Subjects
SARS-CoV-2, Coronavirus, Rapid review, Respiratory tract infection, Zinc, Miscellaneous systems and treatments, RZ409.7-999
Abstract

Background: The global COVID-19 pandemic has prompted an urgent search for effective interventions. SARS-CoV-2 mortality/morbidity risk increases with age and for those chronic disease co-morbidities, both of which are associated with lower zinc status, as is the risk of infection. Methods: Rapid review methods will be applied to a systematic review of zinc for the prevention or treatment of SARS-CoV-2 and viral respiratory tract infections in humans. Included are published studies reporting randomised and quasi-randomised controlled trials that compare zinc intervention to placebo and/or other comparator interventions. English and Chinese language databases will be searched for primary studies of viral respiratory tract infections and clinical trial registries for SARS-CoV-2 infections. Due to concerns about indirectness, studies evaluating non-SARS-CoV-2 coronavirus infections will be rated down by one level, and non-specific or confirmed non-coronavirus viral infections will be rated down by two levels. Review constraints include (1) using Google translate when screening articles published in languages other than English or Chinese and limited translation (2) following calibration, only one reviewer will screen articles, extract data, appraise quality and conduct the analysis, (3) prioritising data extraction and meta-analyses of SARS-CoV-2 studies and critical outcomes of other viral infections, followed by high risk groups and (4) reporting important preliminary findings prior to peer review if necessary. Discussion: The application of these rapid review methods and broadening the inclusion criteria to include other coronavirus-related viral respiratory tract infections aims to enable a timely evidence appraisal of priority research questions and dissemination of results. Study registration: PROSPERO CRD42020182044.

Published
2020
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23. Nutritional supplements and herbal medicines for women with polycystic ovary syndrome; a systematic review and meta-analysis

Author

Susan Arentz, Caroline A. Smith, Jason Abbott, and Alan Bensoussan

Subjects
Polycystic ovary syndrome, PCOS, Supplements, Vitamins, Herbal medicine, Complementary medicine, Other systems of medicine, RZ201-999
Abstract

Abstract Background Polycystic ovary syndrome (PCOS) is a common, reproductive endocrinopathy associated with serious short and long term health risks. Many women with PCOS use ingestible complementary medicines. This systematic review examined the effect on menstrual regulation and adverse effects from randomised controlled trials. Methods Randomised controlled trials (RCTs) that compared herbal or nutritional supplements to placebo or active controls in women with PCOS were eligible for inclusion. Electronic databases were searched to July 2017. Study selection and assessment of quality were conducted independently by two review authors. Results Twenty four studies (1406 women) investigating seven nutritional supplements and four herbal medicines were included. No one study was assessed as having a low risk of bias. Four trials reported on the primary endpoint menstrual regulation. There was no evidence on improved menstrual regularity for calcium plus vitamin D compared to Metformin (RR: 0.66, 95% CI 0.35 to 1.23, p = 0.19), reduced amenorrhoea for Camellia sinensis compared to placebo (RR: 0.17, 95% CI 0.02 to 1.72, p = 0.13) and no difference in the number of menses per month for Cinnamomum sp. against placebo (MD 0.05, 95% CI -0.36 to 1.36, p = 0.26). Adverse effects were investigated in seven studies (164 women). Mild adverse effects were found for Cinnamomum sp. compared to placebo (17 women, RR: 0.36, 95% CI 0.03 to 0.70, p = 0.03). No difference was found for adverse effects between inositol, B complex vitamins, vitamin D, chromium and placebo. Improved reproduction, metabolic hormones and hyperandrogenism was found for inositol and improved cholesterol for omega three fish oils. Conclusion There is no high quality evidence to support the effectiveness of nutritional supplements and herbal medicine for women with PCOS and evidence of safety is lacking. High quality trials of nutritional supplements and herbal medicines examining menstrual regulation and adverse effects in women with PCOS are needed.

Published
2017
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