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7Th International Congress on Amino Acids and Proteins Vienna, Austria

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Amino Acids (2001) 21: 1–90 7th International Congress on Amino Acids and Proteins Vienna, Austria August 6–10, 2001 Abstracts Co-Presidents: Steve Schaffer, Mobilel, AL, U.S.A. Michael Fountoulakis, Basel, Switzerland Gert Lubec, Vienna, Austria Contents Analysis................................................................................ 3 Biology ................................................................................ 10 Proteomics . 14 Medicine . 22 Metabolism/Nutrition . 25 Neurobiology . 35 Neuroscience . 45 Plant Amino Acids . 56 Physiology/Exercise and Sport . 59 Polyamines . 63 Synthesis . 68 Taurine ................................................................................ 74 Amino Acids Transport . 79 Addendum . 86 3 Analysis Fully automated HPLC based analysis of cysteine and related used for calculation of the degree of substitution in case of compounds in plasma using on line microdialysis as sample peptide-conjugates. The results of amino acid analysis were preparation verified by the data of ES mass spectrometry method. [This study was supported by grants from Hungarian E. Bald Research Fund (OTKA) T 030838, T025834, T032425, F034886 Department of Environmental Chemistry, University of ´Lodz´, and from the Ministry of Education (FKFP/0153/2001).] Poland Low molecular weight thiols play important roles in metabolism and homeostasis. While plasma thiols, including Free and bound cysteine in homocystinuria: assessment of metabolically related cysteine, glutathione, and homocysteine, cysteine and glutathione status are being investigated as potential indicators of health status A. Briddon1, I. P. Hargreaves1, and P. J. Lee2 and disease risk, trace levels, poor stability, and the lack of 1 structural properties necessary for the production of signals Department of Clinical Biochemistry, and compatible with common detection methods have hampered 2 Metabolic Unit, The National Hospital for Neurology and their accurate assessment. The facile oxidation of sulfhydryl Neurosurgery, London, U.K. compounds results in a variety of disulfide forms in vivo. To The raised concentration of protein bound homocysteine in determine total plasma thiols – the sum of protein-bound forms, homocystinuric (HCU) patients displaces protein bound oxidized low-molecular-mass forms, and free reduced thiols – it cysteine and increases the free/bound cysteine ratio in plasma. is necessary to reduce disulfide bonds. In this presentation, a This ratio is independent of albumin concentration. Results new procedure for fully automated assay of total cysteine, from 31HCU patients were compared to 40 controls. Free cys- cysteinylglycine, glutathione, and homocysteine in human tine concentrations in HCU were poorly discriminated from the plasma is outlined. The oxidized and protein-bound thiols frac- control range but the total cysteine results were almost invari- tions are converted into their reduced forms employing sodium ably lower than control data. This appears to result from an borohydride, and following derivatization with 2-chloro-1- increased free/bound cysteine ratio in HCU [mean (range) for methylquinolinium tetrafluoroborate and deproteinization by control 0.50 (0.22–0.71) and for HCU 0.76 (0.32–1.75); P 5 on line microdialysis, the S-quinolinium derivatives of analytes 0.0005]. Ex vivo protein binding experiments in albumin solu- are separated, from each other and internal standard, and quan- tion revealed the free/bound cysteine ratio to be linearly related tified by ion-pair reversed-phase HPLC with ultraviolet detec- to the amount of homocysteine bound (r 5 0.907, P , 0.001). tion. The whole unattended instrument acquisition time is We conclude that measurement of total cysteine is essential for 13min with no manual processing of sample. As a result about assessment of the true cysteine status in HCU. However, any 80 samples a day can be assayed for total cysteine and related cysteine deficit, or alteration to free/bound cysteine ratios, does compounds. The method is linear within the normal and patho- not obviously effect glutathione synthesis as assessed by mea- logical ranges of thiols in humans and its sensitivity, precision surement of plasma total glutathione. and accuracy fulfils experimental and clinical requirements. Free D-amino acids in vertebrates Determination of S-carboxymethyl-cysteine in cyclo-peptides 1 1 2 and peptide-conjugates containing thioether bond H. Brückner , R. Paetzold , and A. Schieber 1 Interdisciplinary Research Center, Institute of Nutritional 1 1 1 S. Bo´´sze , G. Mezo´´ , H. Medzihradszky-Schweiger , Science, Department of Food Sciences, University of Z. Skribanek2, and F. Hudecz1 Giessen, and 1 Research Group of Peptide Chemistry, Hungarian Academy 2 Institute of Food Technology, Section Plant Foodstuff of Sciences, Eötvös L. University, Budapest, and Technology, University of Hohenheim, Stuttgart, Germany 2 Gedeon Richter Ltd., Budapest, Hungary In continuation of work on the screening of mammals for Chemically stable thioether bond is frequently applied for the occurrence of free D-amino acids (D-AAs), here we present the preparation of cyclopeptides and of peptide-conjugates pos- data on quantities determined in urine and blood plasma of sessing free SH group in one of the partner molecules. For the guinea pig, rabbit, goat, dromedary and cat, in the blood serum introduction of such bond the free thiol group of cysteine reacts of fish, and in the brains of mole rat, rabbit, pig, bovine, seal, with haloacetyl group attached to amino function of N-terminal and rob. AAs were isolated by cation exchanger, converted amino acid or lysine side chain of the peptide. The homogeneity into their N(O)-pentafluoro amino acid 2-propyl esters and and the amino acid composition of new compounds was quantified on a Chirasil-L-Val capillary column using mass checked by amino acid analysis, analytical RP-HPLC and mass spectrometric detection as described. spectrometry. Qualitative and quantitative determination of Representative data of animals investigated (n 5 2–3) are S-carboxymethyl-cysteine (SMC) derived from this thioether shown in the Table. As can be seen free D-AAs were detected linkage containing moiety was developed. Prior to amino acid in the orders Rodentia (Cavia aperea f. porcellus, guinea pig); analysis samples were hydrolysed in 6N HCl in sealed and Lagomorpha (Oryctolagus cuniculus f. domestica, rabbit); evacuated tubes at 110°C for 24, 36 or 48hrs depending on the Artiodactyla (Capra aegagrus f. hircus, goat); Artiodactyla structure of molecules. The amino acid composition of the com- (Camelus dromedaries, dromedary); Carnivora (Felis libyca f. pounds was determined by two independent methods: using catus, cat); and Osteichthyes (Gadus morrhua, codfish). Largest pre-column derivatization with o-phtaldialdehyde (OPA) rea- amounts of D-AAs were excreted with the urine. Free D-Ser gent and post-column derivatization with ninhydrin. The ap- (% relative to L-Ser) was detected in the brains (n 5 1–2; pearance of SCM verified the success of cyclization and can be cerebrum, wet weight) of mole (Talpa europaea, Insectivora) 4 Table 1. Quantities of D-amino acids (D-AA) in body fluids of vertebrates [% D 5 100 D/(D 1 L)] guinea rabbit goat piga) urine urine serum urine plasma D-AA µmol/L %D µmol/L %D µmol/L %D µmol/L %D µmol/L %D Ala 452.9 61.9 50.2 53.5 3.4 1.3 3.7 5.2 0.5 1.0 Val 30.7 10.9 1.2 4.4 – – – – – – Thr 96.1 15.3 – – – – – 0.4 – – Pro 3.2 1.4 2.3 2.9 0.5 0.2 – 2.9 ,0.1 0.1 Ser 99.5 27.2 245.4 69.8 2.5 0.9 2.5 12.6 0.2 0.9 Asx 17.9 11.8 31.5 30.2 1.1 1.1 4.0 16.5 0.1 2.3 Met 49.3 68.4 – – – – – – – – Phe – – 4.3 15.2 – – – – – – Glx 71.7 8.5 18.0 13.1 0.8 0.2 11.7 8.8 0.2 0.1 Tyr – – 16.9 26.8 – – – – – – Orn 89.7 33.7 9.0 19.5 0.6 0.7 0.2 3.0 – – Lys 0.9 9.7 7.3 2.5 0.8 0.7 0.2 0.6 0.7 1.7 dromedary cata) codfish urine serum urine serum serumb) D-AA µmol/L %D µmol/L %D µmol/L %D µmol/L %D nmol/L %D Ala 2.5 11.3 4.2 0.6 57.9 32.0 4.0 0.5 46 0.5 Val – – – – 7.4 9.9 – – – – Thr – – – – 4.2 1.4 – – – – Pro 0.5 1.9 – – 0.9 4.4 1.5 0.8 12 0.4 Ser 2.9 7.9 – – 159.9 61.6 2.0 0.8 – – Asx 3.9 14.8 1.8 1.2 18.4 50.9 1.0 2.0 27 4.3 Met – – – – 164.8 49.4 – – – – Phe– ––––––––– Glx 14.7 18.8 1.5 0.2 28.3 5.3 2.6 0.2 43 0.9 Tyr– ––––1.5–––– Orn 1.9 5.8 – – 12.6 32.5 – – 8 1.7 Lys 0.5 1.2 1.4 0.7 61.4 23.0 1.2 0.4 41 0.7 (2) refers to not detected or not determinable; Asx 5 Asp 1 Asn; Glx 5 Glu 1 Gln; His, Arg, Trp, Cys not determined; a) feed fortified with DL-Met; b) nmol/g lyophilized serum. (339nmol/g; 21.6%); Sprague-Dawley rat (Rattus norvegicus, Rodentia) (n 5 6; 98–381nmol/g; 9.8–13.7%); rabbit (152nmol/ The hydrolysis method was extensively studied, in several g; 11.3%); pig (Sus scrofa f. domestica, Artiodactyla) (221nmol/ time/temperature combinations, in order to avoid racemization. g; 13.4%); bovine (Bos primigenius f. taurus, Artiodactyla) The classical HCl 6M with and without phenol was tested as (284nmol/g; 23.6%); seal (Phoca vitulina, Carnivora) well as methylsulfonic acid 4M, described as producing less (136nmol/g; 3.8%), and rob (Halichoerus grypus, Carnivora) racemization. Indeed, the last acid induced less formation of the (218nmol/g; 5.4%). From the date it is concluded that D-AAs D-aminoacids.
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  • Brain CYP2D6 and Its Role in Neuroprotection Against Parkinson's

    Brain CYP2D6 and Its Role in Neuroprotection Against Parkinson's

    Brain CYP2D6 and its role in neuroprotection against Parkinson’s disease by Amandeep Mann A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Graduate Department of Pharmacology and Toxicology University of Toronto © Copyright by Amandeep Mann 2011 Brain CYP2D6 and its role in neuroprotection against Parkinson’s disease Amandeep Mann Doctor of Philosophy, 2011 Graduate Department of Pharmacology and Toxicology University of Toronto Abstract The enzyme CYP2D6 can metabolize many centrally acting drugs and endogenous neural compounds (e.g. catecholamines); it can also inactivate neurotoxins such as 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1,2,3,4-tetrahydroisoquinoline (TIQ) and β- carbolines that have been associated with Parkinson’s disease (PD). CYP2D6 is ideally situated in the brain to inactivate these neurotoxins. The CYP2D6 gene is also highly polymorphic, which leads to large variation in substrate metabolism. Furthermore, CYP2D6 genetically poor metabolizers are known to be at higher risk for developing PD, a risk that increases with exposure to pesticides. Conversely, smokers have a reduced risk for PD and smokers are suggested to have higher brain CYP2D6 levels. Our studies furthered the characterization and involvement of CYP2D6 in neuroprotection against PD. METHODS: We investigated the effects of CYP2D6 inhibition on MPP+-induced cell death in SH-SHY5Y human neuroblastoma cells. We compared levels of brain CYP2D6, measured by western blotting, between human smokers and non-smokers, between African Green monkeys treated with saline or nicotine, and between PD cases and controls. In addition, we assessed changes in human brain CYP2D6 expression with age.
  • VDAC1 Is Essential for Neurite Maintenance and the Inhibition Of

    VDAC1 Is Essential for Neurite Maintenance and the Inhibition Of

    www.nature.com/scientificreports OPEN VDAC1 is essential for neurite maintenance and the inhibition of its oligomerization protects Received: 4 July 2019 Accepted: 4 September 2019 spinal cord from demyelination Published: xx xx xxxx and facilitates locomotor function recovery after spinal cord injury Vera Paschon1, Beatriz Cintra Morena1, Felipe Fernandes Correia1, Giovanna Rossi Beltrame1, Gustavo Bispo dos Santos2, Alexandre Fogaça Cristante2 & Alexandre Hiroaki Kihara 1 During the progression of the neurodegenerative process, mitochondria participates in several intercellular signaling pathways. Voltage-dependent anion-selective channel 1 (VDAC1) is a mitochondrial porin involved in the cellular metabolism and apoptosis intrinsic pathway in many neuropathological processes. In spinal cord injury (SCI), after the primary cell death, a secondary response that comprises the release of pro-infammatory molecules triggers apoptosis, infammation, and demyelination, often leading to the loss of motor functions. Here, we investigated the functional role of VDAC1 in the neurodegeneration triggered by SCI. We frst determined that in vitro targeted ablation of VDAC1 by specifc morpholino antisense nucleotides (MOs) clearly promotes neurite retraction, whereas a pharmacological blocker of VDAC1 oligomerization (4, 4′-diisothiocyanatostilbene-2, 2′-disulfonic acid, DIDS), does not cause this efect. We next determined that, after SCI, VDAC1 undergoes conformational changes, including oligomerization and N-terminal exposition, which are important steps in the triggering of apoptotic signaling. Considering this, we investigated the efects of DIDS in vivo application after SCI. Interestingly, blockade of VDAC1 oligomerization decreases the number of apoptotic cells without interfering in the neuroinfammatory response. DIDS attenuates the massive oligodendrocyte cell death, subserving undisputable motor function recovery. Taken together, our results suggest that the prevention of VDAC1 oligomerization might be benefcial for the clinical treatment of SCI.