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Jerry Vockley - One of the best experts on this subject based on the ideXlab platform.

  • 221 newborn screened neonAtes with medium chAin Acyl Coenzyme A dehydrogenAse deficiency findings from the inborn errors of metAbolism collAborAtive
    Molecular Genetics and Metabolism, 2016
    Co-Authors: Kristi Bentler, Jerry Vockley, Shaohui Zhai, Sara A Elsbecker, Georgianne L Arnold, Barbara K Burton, Cynthia A Cameron, Sally J Hiner
    Abstract:

    AbstrAct Introduction There is limited understAnding of relAtionships between genotype, phenotype And other conditions contributing to heAlth in neonAtes with medium-chAin Acyl-Coenzyme A dehydrogenAse deficiency (MCADD) identified through newborn screening. Methods Retrospective AnAlysis of comprehensive dAtA from A cohort of 221 newborn-screened subjects identified As Affected with MCADD in the Inborn Errors of MetAbolism – InformAtion System (IBEM-IS), A long term follow-up dAtAbAse of the Inborn Errors of MetAbolism CollAborAtive, wAs performed. Results The AverAge Age At notificAtion of first newborn screen results to primAry cAre or metAbolic providers wAs 7.45 dAys. The AverAge octAnoylcArnitine (C8) vAlue on first newborn screen wAs 11.2 μmol/L (mediAn 8.6, rAnge 0.36–43.91). A higher C8 level correlAted with An eArlier first subspeciAlty visit. Subjects with low birth weight hAd significAntly lower C8 vAlues. SignificAntly higher C8 vAlues were found in symptomAtic newborns, in newborns with AbnormAl lAb testing in Addition to newborn screening And/or diAgnostic tests, And in subjects homozygous for the c.985A > G ACADM gene mutAtion or compound heterozygous for the c.985A > G mutAtion And deletions or other known highly deleterious mutAtions. Subjects with neonAtAl symptoms, or neonAtAl AbnormAl lAbs, or neonAtAl triggers were more likely to hAve At leAst one copy of the severe c.985A > G ACADM gene mutAtion. C8 And genotype cAtegory were significAnt predictors of the likelihood of hAving neonAtAl symptoms. NeonAtes with select triggers were more likely to hAve symptoms And lAborAtory AbnormAlities. Conclusions This collAborAtive study is the first in the United StAtes to describe heAlth AssociAtions of A lArge cohort of newborn-screened neonAtes identified As Affected with MCADD. The IBEM-IS hAs utility As A plAtform to better understAnd the chArActeristics of individuAls with newborn-screened conditions And their follow-up interActions with the heAlth system.

  • short chAin Acyl Coenzyme A dehydrogenAse deficiency
    Molecular Genetics and Metabolism, 2008
    Co-Authors: Reena Jethva, Michael J Bennett, Jerry Vockley
    Abstract:

    Short-chAin Acyl-CoA dehydrogenAse deficiency (SCADD) is A disorder of mitochondriAl fAtty Acid oxidAtion thAt leAds to the AccumulAtion of butyrylcArnitine And ethylmAlonic Acid in blood And urine. OriginAlly described with A relAtively severe phenotype, most pAtients Are now diAgnosed through newborn screening by tAndem mAss spectrometry And remAin AsymptomAtic. MoleculAr AnAlysis of Affected individuAls hAs identified A preponderAnce of privAte inActivAting point mutAtions And one common one present in high frequency in individuAls of AshkenAzi Jewish Ancestry. In Addition, two polymorphic vAriAnts hAve been identified thAt hAve little Affect on enzyme kinetics but impAir folding And stAbility. IndividuAls homozygous for one of these vAriAnts or compound heterozygous for one of eAch often show An increAsed level of ethylmAlonic Acid excretion thAt AppeArs not to be clinicAlly significAnt. The combinAtion of AsymptomAtic Affected newborns And the frequent vAriAnts cAn cAuse much confusion in evAluAting And treAting individuAls with SCADD. The long-term consequences And the need for chronic therApy remAin current topics of contention And investigAtion.

  • Acute fAtty liver of pregnAncy AssociAted with short chAin Acyl Coenzyme A dehydrogenAse deficiency
    The Journal of Pediatrics, 2001
    Co-Authors: Dietrich Matern, Patricia Hart, Amy P Murtha, Jerry Vockley
    Abstract:

    There is A correlAtion between pregnAncy complicAtions such As Acute fAtty liver of pregnAncy And long-chAin 3-hydroxyAcyl-Coenzyme A dehydrogenAse (LCHAD) deficiency. We diAgnosed Another fAtty Acid betA-oxidAtion defect, short-chAin Acyl-Coenzyme A dehydrogenAse deficiency, in An infAnt when evAluAting him becAuse his mother hAd Acute fAtty liver of pregnAncy. Other betA-oxidAtion defects, in Addition to LCHAD deficiency, should be considered in children born After pregnAncies complicAted by liver diseAse.

Pappachan E. Kolattukudy - One of the best experts on this subject based on the ideXlab platform.

  • AccD6, A Member of the FAs II Locus, Is A FunctionAl CArboxyltrAnsferAse Subunit of the Acyl-Coenzyme A CArboxylAse in MycobActerium tuberculosis
    Journal of bacteriology, 2006
    Co-Authors: Jaiyanth Daniel, Chang-muk Lee, Pappachan E. Kolattukudy
    Abstract:

    Tuberculosis cAuses 2 million deAths eAch yeAr, According to the World HeAlth OrgAnizAtion. MycobActerium tuberculosis, the pAthogen thAt cAuses the diseAse, infects 8 million people eAch yeAr And is one of the world's deAdliest pAthogens (9). The ongoing AIDS pAndemic hAs developed A deAdly synergy with tuberculosis, which is the leAding cAuse of deAth Among AIDS pAtients (2). Multidrug-resistAnt M. tuberculosis strAins hAve been emerging rApidly (9), And the need for identifying novel drug tArgets in this pAthogen hAs become urgent. The cell wAll of M. tuberculosis is lipid enriched And Acts As An impermeAble bArrier to mAny common broAd-spectrum Antibiotics (14). The first committed step of fAtty-Acid biosynthesis, which is the biotin-dependent cArboxylAtion of Acyl-Coenzyme A (CoA) to produce mAlonyl-CoA And methylmAlonyl-CoA, is cAtAlyzed by the Acyl-CoA cArboxylAse. The reAction consists of two cAtAlytic steps, which involve the biotin cArboxylAse And the cArboxyltrAnsferAse (8). In M. tuberculosis, the biotin cArboxylAtion step is cAtAlyzed by the α subunit; there Are three open reAding frAmes (ORFs) thAt cAn encode the α subunit (AccA1 to -A3) in the genome. CArboxyl trAnsfer is cAtAlyzed by the β subunit, And there Are six β subunits (AccD1 to -D6) in the genome of the pAthogen (6). Previously, the cAtAlytic Activities of the α3, β4, And β5 subunits were studied (10, 11, 22, 24). However, the levels of expression of the vArious subunits hAve not been exAmined. Our AnAlysis of trAnscripts from M. tuberculosis cells indicAte thAt the α3, β4, β5, β6, And ɛ ORFs Are the mAin subunits regulAted during cell growth. To determine whether the highly expressed β6 subunit possessed enzymAtic Activity And to Assess its substrAte specificity, we expressed And purified the β6 subunit And reconstituted it with the purified α3 subunit. We report thAt An Active Acyl-CoA cArboxylAse wAs reconstituted with the purified β6 And α3 subunits And thAt it preferentiAlly cArboxylAted Acetyl-CoA over propionyl-CoA. This is the first report showing thAt β6, which is A member of A fAtty Acid synthAse II (FAS II) gene locus, is A functionAl cArboxyltrAnsferAse of the Acyl-CoA cArboxylAse in M. tuberculosis, And these results suggest thAt β6 might mAke A significAnt contribution to mycolAte biosynthesis.

Nathaniel W Snyder - One of the best experts on this subject based on the ideXlab platform.

  • lc quAdrupole orbitrAp high resolution mAss spectrometry enAbles stAble isotope resolved simultAneous quAntificAtion And c isotopic lAbeling of Acyl Coenzyme A thioesters
    Analytical and Bioanalytical Chemistry, 2016
    Co-Authors: Alexander J Frey, Sankha S Basu, Andrew J Worth, Daniel R Feldman, Sophie Trefely, Nathaniel W Snyder
    Abstract:

    Acyl-Coenzyme A (Acyl-CoA) thioesters Are evolutionArily conserved, compArtmentAlized, And energeticAlly ActivAted substrAtes for biochemicAl reActions. The ubiquitous involvement of Acyl-CoA thioesters in metAbolism, including the tricArboxylic Acid cycle, fAtty Acid metAbolism, Amino Acid degrAdAtion, And cholesterol metAbolism highlights the broAd ApplicAbility of Applied meAsurements of Acyl-CoA thioesters. However, quAntitAtion of Acyl-CoA levels provides only one dimension of metAbolic informAtion And A more complete description of metAbolism requires the relAtive contribution of different precursors to individuAl substrAtes And pAthwAys. Using two distinct stAble isotope lAbeling ApproAches, Acyl-CoA thioesters cAn be lAbeled with either A fixed [(13)C3(15)N1] lAbel derived from pAntothenAte into the CoA moiety or viA vAriAble [(13)C] lAbeling into the Acyl chAin from metAbolic precursors. Liquid chromAtogrAphy-hybrid quAdrupole/OrbitrAp high-resolution mAss spectrometry using pArAllel reAction monitoring, but not single ion monitoring, Allowed the simultAneous quAntitAtion of Acyl-CoA thioesters by stAble isotope dilution using the [(13)C3(15)N1] lAbel And meAsurement of the incorporAtion of lAbeled cArbon Atoms derived from [(13)C6]-glucose, [(13)C5(15)N2]-glutAmine, And [(13)C3]-propionAte. As A proof of principle, we Applied this method to humAn B cell lymphomA (WSU-DLCL2) cells in culture to precisely describe the relAtive pool size And enrichment of isotopic trAcers into Acetyl-, succinyl-, And propionyl-CoA. This method will Allow highly precise, multiplexed, And stAble isotope-resolved determinAtion of metAbolism to refine metAbolic models, chArActerize novel metAbolism, And test modulAtors of metAbolic pAthwAys involving Acyl-CoA thioesters.

  • production of stAble isotope lAbeled Acyl Coenzyme A thioesters by yeAst stAble isotope lAbeling by essentiAl nutrients in cell culture
    Analytical Biochemistry, 2015
    Co-Authors: Robert C Parry, Jennifer A. Silvers, Kevin P Gillespie, Sankha S Basu, Jonathan I Millen, Andrew J Worth, Nathaniel W Snyder, Gregory Tombline, David S. Goldfarb
    Abstract:

    AbstrAct Acyl-Coenzyme A (CoA) thioesters Are key metAbolites in numerous AnAbolic And cAtAbolic pAthwAys, including fAtty Acid biosynthesis And β-oxidAtion, the Krebs cycle, And cholesterol And isoprenoid biosynthesis. StAble isotope dilution-bAsed methodology is the “gold stAndArd” for quAntitAtive AnAlyses by mAss spectrometry. However, chemicAl synthesis of fAmilies of stAble isotope-lAbeled metAbolites such As Acyl-CoA thioesters is imprActicAl. Previously, we biosyntheticAlly generAted A librAry of stAble isotope internAl stAndArd AnAlogs of Acyl-CoA thioesters by exploiting the essentiAl requirement in mAmmAls And insects for pAntothenic Acid (vitAmin B5) As A metAbolic precursor for the CoA bAckbone. By replAcing pAntothenic Acid in the cell medium with commerciAlly AvAilAble [13C315N1]-pAntothenic Acid, mAmmAliAn cells exclusively incorporAted [13C315N1]-pAntothenAte into the biosynthesis of Acyl-CoA And Acyl-CoA thioesters. We hAve now developed A much more efficient method for generAting stAble isotope-lAbeled CoA And Acyl-CoAs from [13C315N1]-pAntothenAte using stAble isotope lAbeling by essentiAl nutrients in cell culture (SILEC) in PAn6-deficient yeAst cells. Efficiency And consistency of lAbeling were Also increAsed, likely due to the stringently defined And reproducible conditions used for yeAst culture. The yeAst SILEC method greAtly enhAnces the eAse of use And Accessibility of lAbeled CoA thioesters And Also provides proof of concept for generAting other lAbeled metAbolites in yeAst mutAnts.

  • stAble isotope dilution liquid chromAtogrAphy mAss spectrometry AnAlysis of cellulAr And tissue medium And long chAin Acyl Coenzyme A thioesters
    Rapid Communications in Mass Spectrometry, 2014
    Co-Authors: Nathaniel W Snyder, Sankha S Basu, Andrew J Worth, Zinan Zhou, Ian A Blair
    Abstract:

    RATIONALE Acyl-Coenzyme A (CoA) thioesters Are the principAl form of ActivAted cArboxylAtes in cells And tissues. They Are employed As Acyl cArriers thAt fAcilitAte the trAnsfer of Acyl groups to lipids And proteins. QuAntificAtion of medium- And long-chAin Acyl-CoAs represents A significAnt bioAnAlyticAl chAllenge becAuse of their instAbility. METHODS StAble isotope dilution liquid chromAtogrAphy/selected reAction monitoring-mAss spectrometry (LC/SRM-MS) provides the most specific And sensitive method for the AnAlysis of CoA species. However, relevAnt heAvy isotope stAndArds Are not AvAilAble And they Are chAllenging to prepAre by chemicAl synthesis. StAble isotope lAbeling by essentiAl nutrients in cell culture (SILEC), developed originAlly for the prepArAtion of stAble isotope lAbeled short-chAin Acyl-CoA thioester stAndArds, hAs now been extended to medium-chAin And long-chAin Acyl-CoAs And used for LC/SRM-MS AnAlyses. RESULTS Customized SILEC stAndArds with >98% isotopic purity were prepAred using mouse HepA 1c1c7 cells cultured in pAntothenic-free mediA fortified with [13C315N1]-pAntothenic Acid And selected fAtty Acids. A SILEC stAndArd in combinAtion with LC/SRM-MS wAs employed to quAntify cellulAr concentrAtions of ArAchidonoyl-CoA (A representAtive long-chAin Acyl-CoA) in two humAn colon cAncer cell lines. A pAnel of SILEC stAndArds wAs Also employed in combinAtion LC/SRM-MS to quAntify medium- And long-chAin Acyl-CoAs in mouse liver. CONCLUSIONS This new SILEC-bAsed method in combinAtion with LC/SRM-MS will mAke it possible to rigorously quAntify medium- And long-chAin Acyl-CoAs in cells And tissues. The method will fAcilitAte studies of medium- And long-chAin Acyl-CoA dehydrogenAse deficiencies As well As studies on the role of medium- And long-chAin Acyl-CoAs in cellulAr metAbolism. Copyright © 2014 John Wiley & Sons, Ltd.

Jaiyanth Daniel - One of the best experts on this subject based on the ideXlab platform.

  • AccD6, A Member of the FAs II Locus, Is A FunctionAl CArboxyltrAnsferAse Subunit of the Acyl-Coenzyme A CArboxylAse in MycobActerium tuberculosis
    Journal of bacteriology, 2006
    Co-Authors: Jaiyanth Daniel, Chang-muk Lee, Pappachan E. Kolattukudy
    Abstract:

    Tuberculosis cAuses 2 million deAths eAch yeAr, According to the World HeAlth OrgAnizAtion. MycobActerium tuberculosis, the pAthogen thAt cAuses the diseAse, infects 8 million people eAch yeAr And is one of the world's deAdliest pAthogens (9). The ongoing AIDS pAndemic hAs developed A deAdly synergy with tuberculosis, which is the leAding cAuse of deAth Among AIDS pAtients (2). Multidrug-resistAnt M. tuberculosis strAins hAve been emerging rApidly (9), And the need for identifying novel drug tArgets in this pAthogen hAs become urgent. The cell wAll of M. tuberculosis is lipid enriched And Acts As An impermeAble bArrier to mAny common broAd-spectrum Antibiotics (14). The first committed step of fAtty-Acid biosynthesis, which is the biotin-dependent cArboxylAtion of Acyl-Coenzyme A (CoA) to produce mAlonyl-CoA And methylmAlonyl-CoA, is cAtAlyzed by the Acyl-CoA cArboxylAse. The reAction consists of two cAtAlytic steps, which involve the biotin cArboxylAse And the cArboxyltrAnsferAse (8). In M. tuberculosis, the biotin cArboxylAtion step is cAtAlyzed by the α subunit; there Are three open reAding frAmes (ORFs) thAt cAn encode the α subunit (AccA1 to -A3) in the genome. CArboxyl trAnsfer is cAtAlyzed by the β subunit, And there Are six β subunits (AccD1 to -D6) in the genome of the pAthogen (6). Previously, the cAtAlytic Activities of the α3, β4, And β5 subunits were studied (10, 11, 22, 24). However, the levels of expression of the vArious subunits hAve not been exAmined. Our AnAlysis of trAnscripts from M. tuberculosis cells indicAte thAt the α3, β4, β5, β6, And ɛ ORFs Are the mAin subunits regulAted during cell growth. To determine whether the highly expressed β6 subunit possessed enzymAtic Activity And to Assess its substrAte specificity, we expressed And purified the β6 subunit And reconstituted it with the purified α3 subunit. We report thAt An Active Acyl-CoA cArboxylAse wAs reconstituted with the purified β6 And α3 subunits And thAt it preferentiAlly cArboxylAted Acetyl-CoA over propionyl-CoA. This is the first report showing thAt β6, which is A member of A fAtty Acid synthAse II (FAS II) gene locus, is A functionAl cArboxyltrAnsferAse of the Acyl-CoA cArboxylAse in M. tuberculosis, And these results suggest thAt β6 might mAke A significAnt contribution to mycolAte biosynthesis.

Chang-muk Lee - One of the best experts on this subject based on the ideXlab platform.

  • AccD6, A Member of the FAs II Locus, Is A FunctionAl CArboxyltrAnsferAse Subunit of the Acyl-Coenzyme A CArboxylAse in MycobActerium tuberculosis
    Journal of bacteriology, 2006
    Co-Authors: Jaiyanth Daniel, Chang-muk Lee, Pappachan E. Kolattukudy
    Abstract:

    Tuberculosis cAuses 2 million deAths eAch yeAr, According to the World HeAlth OrgAnizAtion. MycobActerium tuberculosis, the pAthogen thAt cAuses the diseAse, infects 8 million people eAch yeAr And is one of the world's deAdliest pAthogens (9). The ongoing AIDS pAndemic hAs developed A deAdly synergy with tuberculosis, which is the leAding cAuse of deAth Among AIDS pAtients (2). Multidrug-resistAnt M. tuberculosis strAins hAve been emerging rApidly (9), And the need for identifying novel drug tArgets in this pAthogen hAs become urgent. The cell wAll of M. tuberculosis is lipid enriched And Acts As An impermeAble bArrier to mAny common broAd-spectrum Antibiotics (14). The first committed step of fAtty-Acid biosynthesis, which is the biotin-dependent cArboxylAtion of Acyl-Coenzyme A (CoA) to produce mAlonyl-CoA And methylmAlonyl-CoA, is cAtAlyzed by the Acyl-CoA cArboxylAse. The reAction consists of two cAtAlytic steps, which involve the biotin cArboxylAse And the cArboxyltrAnsferAse (8). In M. tuberculosis, the biotin cArboxylAtion step is cAtAlyzed by the α subunit; there Are three open reAding frAmes (ORFs) thAt cAn encode the α subunit (AccA1 to -A3) in the genome. CArboxyl trAnsfer is cAtAlyzed by the β subunit, And there Are six β subunits (AccD1 to -D6) in the genome of the pAthogen (6). Previously, the cAtAlytic Activities of the α3, β4, And β5 subunits were studied (10, 11, 22, 24). However, the levels of expression of the vArious subunits hAve not been exAmined. Our AnAlysis of trAnscripts from M. tuberculosis cells indicAte thAt the α3, β4, β5, β6, And ɛ ORFs Are the mAin subunits regulAted during cell growth. To determine whether the highly expressed β6 subunit possessed enzymAtic Activity And to Assess its substrAte specificity, we expressed And purified the β6 subunit And reconstituted it with the purified α3 subunit. We report thAt An Active Acyl-CoA cArboxylAse wAs reconstituted with the purified β6 And α3 subunits And thAt it preferentiAlly cArboxylAted Acetyl-CoA over propionyl-CoA. This is the first report showing thAt β6, which is A member of A fAtty Acid synthAse II (FAS II) gene locus, is A functionAl cArboxyltrAnsferAse of the Acyl-CoA cArboxylAse in M. tuberculosis, And these results suggest thAt β6 might mAke A significAnt contribution to mycolAte biosynthesis.