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

  • 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.

Suzanne Jackowski - One of the best experts on this subject based on the ideXlab platform.

  • AntimAlAriAl pAntothenAmide metAbolites tArget Acetyl Coenzyme A biosynthesis in plAsmodium fAlcipArum
    Science Translational Medicine, 2019
    Co-Authors: Joost Schalkwijk, Suzanne Jackowski, Erik L Allman, Patrick A M Jansen, Laura E De Vries, Julie M J Verhoef, Peter N M Botman, Christien A Beuckensschortinghuis, Karin M J Koolen, Judith M Bolscher
    Abstract:

    MAlAriA erAdicAtion is criticAlly dependent on new therApeutics thAt tArget resistAnt PlAsmodium pArAsites And block trAnsmission of the diseAse. Here, we report thAt pAntothenAmide bioisosteres were Active AgAinst blood-stAge PlAsmodium fAlcipArum pArAsites And Also blocked trAnsmission of sexuAl stAges to the mosquito vector. These compounds were resistAnt to degrAdAtion by serum pAntetheinAses, showed fAvorAble phArmAcokinetic properties, And cleAred pArAsites in A humAnized mouse model of P. fAlcipArum infection. MetAbolomics reveAled thAt Coenzyme A biosynthetic enzymes converted pAntothenAmides into Coenzyme A AnAlogs thAt interfered with pArAsite Acetyl-Coenzyme A AnAbolism. ResistAnt pArAsites generAted in vitro showed mutAtions in Acetyl-Coenzyme A synthetAse And Acyl-Coenzyme A synthetAse 11. Introduction And reversion of these mutAtions in P. fAlcipArum using CRISPR-CAs9 gene editing confirmed the roles of these enzymes in the sensitivity of the mAlAriA pArAsites to pAntothenAmides. These pAntothenAmide compounds with A new mode of Action mAy hAve potentiAl As drugs AgAinst mAlAriA pArAsites.

  • impAired Coenzyme A metAbolism Affects histone And tubulin AcetylAtion in drosophilA And humAn cell models of pAntothenAte kinAse AssociAted neurodegenerAtion
    Embo Molecular Medicine, 2011
    Co-Authors: Katarzyna Siudeja, Suzanne Jackowski, Balaji Srinivasan, Anil Rana, Jannie De Jong, Ellen A A Nollen, Lynn Sanford, Susan J Hayflick, Ody C M Sibon
    Abstract:

    PAntothenAte kinAse-AssociAted neurodegenerAtion (PKAN is A neurodegenerAtive diseAse with unresolved pAthophysiology. Previously, we observed reduced Coenzyme A levels in A DrosophilA model for PKAN. Coenzyme A is required for Acetyl-Coenzyme A synthesis And Acyl groups from the lAtter Are trAnsferred to lysine residues of proteins, in A reAction regulAted by AcetyltrAnsferAses. The tight bAlAnce between AcetyltrAnsferAses And their AntAgonistic counterpArts histone deAcetylAses is A well-known determining fActor for the AcetylAtion stAtus of proteins. However, the influence of Coenzyme A levels on protein AcetylAtion is unknown. Here we investigAte whether decreAsed levels of the centrAl metAbolite Coenzyme A induce AlterAtions in protein AcetylAtion And whether this correlAtes with specific phenotypes of PKAN models. We show thAt in vArious orgAnisms proper Coenzyme A metAbolism is required for mAintenAnce of histone- And tubulin AcetylAtion, And decreAsed AcetylAtion of these proteins is AssociAted with An impAired DNA dAmAge response, decreAsed locomotor function And decreAsed survivAl. DecreAsed protein AcetylAtion And the concurrent phenotypes Are pArtly rescued by pAntethine And HDAC inhibitors, suggesting possible directions for future PKAN therApy development.

  • biosynthesis of pAntothenic Acid And Coenzyme A
    EcoSal Plus, 2007
    Co-Authors: Roberta Leonardi, Suzanne Jackowski
    Abstract:

    PAntothenAte is vitAmin B5 And is the key precursor for the biosynthesis of Coenzyme A (CoA), A universAl And essentiAl cofActor involved in A myriAd of metAbolic reActions, including the synthesis of phospholipids, the synthesis And degrAdAtion of fAtty Acids, And the operAtion of the tricArboxylic Acid cycle. CoA is Also the only source of the phosphopAntetheine prosthetic group for enzymes thAt shuttle intermediAtes between the Active sites of enzymes involved in fAtty Acid, nonribosomAl peptide, And polyketide synthesis. PAntothenAte cAn be synthesized de novo And/or trAnsported into the cell through A pAntothenAtepermeAse. PAntothenAte uptAke is essentiAl for those orgAnisms thAt lAck the genes to synthesize this vitAmin. The intrAcellulAr levels of CoA Are controlled by the bAlAnce between synthesis And degrAdAtion. In pArticulAr, CoA is Assembled in five enzymAtic steps, stArting from the phosphorylAtion of pAntothenAte to phosphopAntothenAtecAtAlyzed by pAntothenAte kinAse, the product of the coAA gene. In some bActeriA, the production of phosphopAntothenAte by pAntothenAte kinAse is the rAte limiting And most regulAted step in the biosynthetic pAthwAy. CoA synthesis AdditionAlly networks with other vitAmin-AssociAted pAthwAys, such As thiAmine And folic Acid.

  • FeedbAck regulAtion of murine pAntothenAte kinAse 3 by Coenzyme A And Coenzyme A thioesters.
    The Journal of biological chemistry, 2005
    Co-Authors: Yong-mei Zhang, Charles O. Rock, Suzanne Jackowski
    Abstract:

    PAntothenAte kinAse cAtAlyzes A key regulAtory step in Coenzyme A biosynthesis, And there Are four mAmmAliAn genes thAt encode isoforms of this enzyme. PAntothenAte kinAse isoform PAnK3 is highly relAted to the previously chArActerized PAnK1betA isoform (79% identicAl, 91% similAr), And these two Almost identicAl proteins Are expressed most highly in the sAme tissues. PAnK1betA And PAnK3 hAd very similAr moleculAr sizes, oligomeric form, cytoplAsmic cellulAr locAtion, And kinetic constAnts for ATP And pAntothenAte. However, these two PAnK isoforms possessed distinct regulAtory properties. PAnK3 wAs significAntly more sensitive to feedbAck regulAtion by Acetyl-CoA (IC50 = 1 microm) thAn PAnK1betA (IC50 = 10 microm), And PAnK3 wAs stringently regulAted by long-chAin Acyl-CoA (IC50 = 2 microm), whereAs PAnK1betA wAs not. DomAin swApping experiments locAlized the difference in the two proteins to A 48-Amino-Acid domAin, where they Are the most divergent. Consistent with these more stringent regulAtory properties, metAbolic lAbeling experiments showed thAt Coenzyme A (CoA) levels in cells overexpressing PAnK3 were lower thAn in cells overexpressing An equivAlent Amount of PAnK1betA. Thus, the distinct regulAtory properties exhibited by the fAmily of the pAntothenAte kinAses Allowed the rAte of CoA biosynthesis to be controlled by regulAtory signAls from CoA thioesters involved in different brAnches of intermediAry metAbolism.

  • Coenzyme A bAck in Action
    Progress in Lipid Research, 2005
    Co-Authors: Roberta Leonardi, Yong-mei Zhang, Charles O. Rock, Suzanne Jackowski
    Abstract:

    Coenzyme A (CoA) is A ubiquitous essentiAl cofActor thAt plAys A centrAl role in the metAbolism of cArboxylic Acids, including short- And long-chAin fAtty Acids. In the lAst few yeArs, All of the genes encoding the CoA biosynthetic enzymes hAve been identified And the structures of severAl proteins in the pAthwAy hAve been determined. CoA is Assembled in five steps from pAntothenic Acid And pAthwAy intermediAtes Are common to both prokAryotes And eukAryotes. In spite of the identicAl biochemistry, remArkAble sequence differences Among some of the prokAryotic And eukAryotic enzymes hAve been reveAled by compArAtive genomics. Renewed interest in CoA hAs Arisen from the reAlizAtion thAt the biosynthetic pAthwAy is A tArget for AntibActeriAl drug discovery And from the unexpected AssociAtion of A humAn neurodegenerAtive disorder with mutAtions in pAntothenAte kinAse. The purpose of this review is to integrAte previous knowledge with the most recent findings in the genetics, enzymology And regulAtion of CoA biosynthesis in bActeriA, plAnts And mAmmAls.

Birgit E Alber - One of the best experts on this subject based on the ideXlab platform.

  • Properties of Succinyl-Coenzyme A:l-MAlAte Coenzyme A TrAnsferAse And Its Role in the Autotrophic 3-HydroxypropionAte Cycle of Chloroflexus AurAntiAcus
    Journal of bacteriology, 2006
    Co-Authors: Silke Friedmann, Astrid Steindorf, Birgit E Alber
    Abstract:

    The phototrophic bActerium Chloroflexus AurAntiAcus uses the 3-hydroxypropionAte cycle for Autotrophic CO2 fixAtion. This cycle stArts with Acetyl-Coenzyme A (CoA) And produces glyoxylAte. GlyoxylAte is An unconventionAl cell cArbon precursor thAt needs speciAl enzymes for AssimilAtion. GlyoxylAte is combined with propionyl-CoA to β-methylmAlyl-CoA, which is converted to citrAmAlAte. Cell extrActs cAtAlyzed the succinyl-CoA-dependent conversion of citrAmAlAte to Acetyl-CoA And pyruvAte, the centrAl cell cArbon precursor. This reAction is due to the combined Action of enzymes thAt were upregulAted during Autotrophic growth, A Coenzyme A trAnsferAse with the use of succinyl-CoA As the CoA donor And A lyAse cleAving citrAmAlyl-CoA to Acetyl-CoA And pyruvAte. Genomic AnAlysis identified A gene coding for A putAtive Coenzyme A trAnsferAse. The gene wAs heterologously expressed in EscherichiA coli And shown to code for succinyl-CoA:d-citrAmAlAte Coenzyme A trAnsferAse. This enzyme, which cAtAlyzes the reAction d-citrAmAlAte + succinyl-CoA → d-citrAmAlyl-CoA + succinAte, wAs purified And studied. It belongs to clAss III of the Coenzyme A trAnsferAse enzyme fAmily, with An AspArtAte residue in the Active site. The homodimeric enzyme composed of 44-kDA subunits wAs specific for succinyl-CoA As A CoA donor but Also Accepted d-mAlAte And itAconAte insteAd of d-citrAmAlAte. The CoA trAnsferAse gene is pArt of A cluster of genes which Are cotrAnscribed, including the gene for d-citrAmAlyl-CoA lyAse. It is proposed thAt the CoA trAnsferAse And the lyAse cAtAlyze the lAst two steps in the glyoxylAte AssimilAtion route.

George Siegel - One of the best experts on this subject based on the ideXlab platform.

  • decreAsed prevAlence of Alzheimer diseAse AssociAted with 3 hydroxy 3 methyglutAryl Coenzyme A reductAse inhibitors
    JAMA Neurology, 2000
    Co-Authors: Benjamin Wolozin, Wendy Kellman, Paul Ruosseau, Gastone G Celesia, George Siegel
    Abstract:

    Context IncreAsing evidence suggests thAt cholesterol plAys A role in the pAthophysiology of Alzheimer diseAse (AD). For instAnce, An elevAted serum cholesterol level hAs been shown to be A risk fActor for AD. Objective To determine whether pAtients tAking 3-hydroxy-3-methylglutAryl Coenzyme A reductAse inhibitors (stAtins), which Are A group of medicines thAt inhibit the synthesis of cholesterol, hAve A lower prevAlence of probAble AD. Design The experiment uses A cross-sectionAl AnAlysis compAring the prevAlence of probAble AD in 3 groups of pAtients from hospitAl records: the entire populAtion, pAtients receiving 3-hydroxy-3-methylglutAryl Coenzyme A reductAse inhibitors (hereAfter referred to As the stAtins), And pAtients receiving medicAtions used to treAt hypertension or cArdiovAsculAr diseAse. PAtients The subjects studied were those included in the computer dAtAbAses of 3 different hospitAls for the yeArs October 1, 1996, through August 31, 1998. MAin Outcome MeAsures DiAgnosis of probAble AD. Results We find thAt the prevAlence of probAble AD in the cohort tAking stAtins during the study intervAl is 60% to 73% ( P Conclusions There is A lower prevAlence of diAgnosed probAble AD in pAtients tAking 2 different 3-hydroxy-3-methylglutAryl Coenzyme A reductAse inhibitors—lovAstAtin And prAvAstAtin. While one cAnnot infer cAusAtive mechAnisms bAsed on these dAtA, this study reveAls An interesting AssociAtion in the dAtA, which wArrAnts further study.

Patricia Hart - One of the best experts on this subject based on the ideXlab platform.

  • 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.