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Article ; Online: Exogenous d-β-hydroxybutyrate lowers blood glucose in part by decreasing the availability of L-alanine for gluconeogenesis.

Soto-Mota, Adrian / Norwitz, Nicholas G / Evans, Rhys D / Clarke, Kieran

Endocrinology, diabetes & metabolism

2021 Volume 5, Issue 1, Page(s) e00300

Abstract: ... greater in people with type 2 diabetes (T2D). On the contrary, L-alanine is a gluconeogenic substrate ... secreted by skeletal muscle at higher levels in people with T2D and infusing of ketones lower circulating L ... alanine blood levels. In this study, we sought to determine whether supplementation with L-alanine would ...

Abstract	Background: Interventions that induce ketosis simultaneously lower blood glucose and the explanation for this phenomenon is unknown. Additionally, the glucose-lowering effect of acute ketosis is greater in people with type 2 diabetes (T2D). On the contrary, L-alanine is a gluconeogenic substrate secreted by skeletal muscle at higher levels in people with T2D and infusing of ketones lower circulating L-alanine blood levels. In this study, we sought to determine whether supplementation with L-alanine would attenuate the glucose-lowering effect of exogenous ketosis using a ketone ester (KE). Methods: This crossover study involved 10 healthy human volunteers who fasted for 24 h prior to the ingestion of 25 g of d-β-hydroxybutyrate (βHB) in the form of a KE drink (ΔG Findings: The KE drinks elevated blood βHB concentrations from negligible levels to 4.52 ± 1.23 mmol/L, lowered glucose from 4.97 ± SD 0.39 to 3.77 ± SD 0.40 mmol/L, and lowered and L-alanine from 0.56 ± SD 0.88 to 0.41 ± SD 0.91 mmol/L. L-alanine in the KE drink elevated blood L-Alanine by 0.68 ± SD 0.15 mmol/L, but had no significant effect on blood βHB, L-glutamine, FFA, lactate, nor C-peptide concentrations. By contrast, L-alanine supplementation significantly attenuated the ketosis-induced drop in glucose from 28% ± SD 8% to 16% ± SD 7% (p < .01). Conclusions: The glucose-lowering effect of acutely elevated βHB is partially due to βHB decreasing L-alanine availability as a substrate for gluconeogenesis.
MeSH term(s)	3-Hydroxybutyric Acid ; Alanine ; Blood Glucose ; Cross-Over Studies ; Diabetes Mellitus, Type 2 ; Gluconeogenesis ; Humans
Chemical Substances	Blood Glucose ; Alanine (OF5P57N2ZX) ; 3-Hydroxybutyric Acid (TZP1275679)
Language	English
Publishing date	2021-11-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2398-9238
ISSN (online)	2398-9238
DOI	10.1002/edm2.300
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Measurement of the branching fractions of B-->D**(l) nu(l) decays in events tagged by a fully reconstructed B meson.

Aubert, B / Bona, M / Karyotakis, Y / Lees, J P / Poireau, V / Prencipe, E / Prudent, X / Tisserand, V / Garra Tico, J / Grauges, E / Lopez, L / Palano, A / Pappagallo, M / Eigen, G / Stugu, B / Sun, L / Abrams, G S / Battaglia, M / Brown, D N /

Cahn, R N / Jacobsen, R G / Kerth, L T / Kolomensky, Yu G / Lynch, G / Osipenkov, I L / Ronan, M T / Tackmann, K / Tanabe, T / Hawkes, C M / Soni, N / Watson, A T / Koch, H / Schroeder, T / Walker, D / Asgeirsson, D J / Fulsom, B G / Hearty, C / Mattison, T S / Mckenna, J A / Barrett, M / Khan, A / Blinov, V E / Bukin, A D / Buzykaev, A R / Druzhinin, V P / Golubev, V B / Onuchin, A P / Serednyakov, S I / Skovpen, Yu I / Solodov, E P / Todyshev, K Yu / Bondioli, M / Curry, S / Eschrich, I / Kirkby, D / Lankford, A J / Lund, P / Mandelkern, M / Martin, E C / Stoker, D P / Abachi, S / Buchanan, C / Gary, J W / Liu, F / Long, O / Shen, B C / Vitug, G M / Yasin, Z / Zhang, L / Sharma, V / Campagnari, C / Hong, T M / Kovalskyi, D / Mazur, M A / Richman, J D / Beck, T W / Eisner, A M / Flacco, C J / Heusch, C A / Kroseberg, J / Lockman, W S / Schalk, T / Schumm, B A / Seiden, A / Wang, L / Wilson, M G / Winstrom, L O / Cheng, C H / Doll, D A / Echenard, B / Fang, F / Hitlin, D G / Narsky, I / Piatenko, T / Porter, F C / Andreassen, R / Mancinelli, G / Meadows, B T / Mishra, K / Sokoloff, M D / Bloom, P C / Ford, W T / Gaz, A / Hirschauer, J F / Nagel, M / Nauenberg, U / Smith, J G / Ulmer, K A / Wagner, S R / Ayad, R / Soffer, A / Toki, W H / Wilson, R J / Altenburg, D D / Feltresi, E / Hauke, A / Jasper, H / Karbach, M / Merkel, J / Petzold, A / Spaan, B / Wacker, K / Kobel, M J / Mader, W F / Nogowski, R / Schubert, K R / Schwierz, R / Sundermann, J E / Volk, A / Bernard, D / Bonneaud, G R / Latour, E / Thiebaux, Ch / Verderi, M / Clark, P J / Gradl, W / Playfer, S / Watson, J E / Andreotti, M / Bettoni, D / Bozzi, C / Calabrese, R / Cecchi, A / Cibinetto, G / Franchini, P / Luppi, E / Negrini, M / Petrella, A / Piemontese, L / Santoro, V / Baldini-Ferroli, R / Calcaterra, A / de Sangro, R / Finocchiaro, G / Pacetti, S / Patteri, P / Peruzzi, I M / Piccolo, M / Rama, M / Zallo, A / Buzzo, A / Contri, R / Lo Vetere, M / Macri, M M / Monge, M R / Passaggio, S / Patrignani, C / Robutti, E / Santroni, A / Tosi, S / Chaisanguanthum, K S / Morii, M / Marks, J / Schenk, S / Uwer, U / Klose, V / Lacker, H M / Bard, D J / Dauncey, P D / Nash, J A / Panduro Vazquez, W / Tibbetts, M / Behera, P K / Chai, X / Charles, M J / Mallik, U / Cochran, J / Crawley, H B / Dong, L / Meyer, W T / Prell, S / Rosenberg, E I / Rubin, A E / Gao, Y Y / Gritsan, A V / Guo, Z J / Lae, C K / Denig, A G / Fritsch, M / Schott, G / Arnaud, N / Béquilleux, J / D'Orazio, A / Davier, M / Firmino da Costa, J / Grosdidier, G / Höcker, A / Lepeltier, V / Le Diberder, F / Lutz, A M / Pruvot, S / Roudeau, P / Schune, M H / Serrano, J / Sordini, V / Stocchi, A / Wormser, G / Lange, D J / Wright, D M / Bingham, I / Burke, J P / Chavez, C A / Fry, J R / Gabathuler, E / Gamet, R / Hutchcroft, D E / Payne, D J / Touramanis, C / Bevan, A J / Clarke, C K / George, K A / Di Lodovico, F / Sacco, R / Sigamani, M / Cowan, G / Flaecher, H U / Hopkins, D A / Paramesvaran, S / Salvatore, F / Wren, A C / Davis, C L / Alwyn, K E / Bailey, D / Barlow, R J / Chia, Y M / Edgar, C L / Jackson, G / Lafferty, G D / West, T J / Yi, J I / Anderson, J / Chen, C / Jawahery, A / Roberts, D A / Simi, G / Tuggle, J M / Dallapiccola, C / Li, X / Salvati, E / Saremi, S / Cowan, R / Dujmic, D / Fisher, P H / Koeneke, K / Sciolla, G / Spitznagel, M / Taylor, F / Yamamoto, R K / Zhao, M / Patel, P M / Robertson, S H / Lazzaro, A / Lombardo, V / Palombo, E / Bauer, J M / Cremaldi, L / Eschenburg, V / Godang, R / Kroeger, R / Sanders, D A / Summers, D J / Zhao, H W / Simard, M / Taras, P / Viaud, F B / Nicholson, H / De Nardo, G / Lista, L / Monorchio, D / Onorato, G / Sciacca, C / Raven, G / Snoek, H L / Jessop, C P / Knoepfel, K J / Lo Secco, J M / Wang, W F / Benelli, G / Corwin, L A / Honscheid, K / Kagan, H / Kass, R / Morris, J P / Rahimi, A M / Regensburger, J J / Sekula, S J / Wong, Q K / Blount, N L / Brau, J / Frey, R / Igonkina, O / Kolb, J A / Lu, M / Rahmat, R / Sinev, N B / Strom, D / Strube, J / Torrence, E / Castelli, G / Gagliardi, N / Margoni, M / Morandin, M / Posocco, M / Rotondo, M / Simonetto, F / Stroili, R / Voci, C / del Amo Sanchez, P / Ben-Haim, E / Briand, H / Calderini, G / Chauveau, J / David, P / Del Buono, L / Hamon, O / Leruste, Ph / Ocariz, J / Perez, A / Prendki, J / Sitt, S / Gladney, L / Biasini, M / Covarelli, R / Manoni, E / Angelini, C / Batignani, G / Bettarini, S / Carpinelli, M / Cervelli, A / Forti, E / Giorgi, M A / Lusiani, A / Marchiori, G / Morganti, M / Neri, N / Paoloni, E / Rizzo, G / Walsh, J J / Lopes Pegna, D / Lu, C / Olsen, J / Smith, A J S / Telnov, A V / Anulli, F / Baracchini, E / Cavoto, G / del Re, D / Di Marco, E / Faccini, R / Ferrarotto, F / Ferroni, F / Gaspero, M / Jackson, P D / Li Gioi, L / Mazzoni, M A / Morganti, S / Piredda, G / Polci, F / Renga, F / Voena, C / Ebert, M / Hartmann, T / Schröder, H / Waldi, R / Adye, T / Franek, B / Olaiya, E O / Wilson, F F / Emery, S / Escalier, M / Esteve, L / Ganzhur, S F / Hamel de Monchenault, G / Kozanecki, W / Vasseur, G / Yèche, Ch / Zito, M / Chen, X R / Liu, H / Park, W / Purohit, M V / White, R M / Wilson, J R / Allen, M T / Aston, D / Bartoldus, R / Bechtle, P / Benitez, J F / Cenci, R / Coleman, J P / Convery, M R / Dingfelder, J C / Dorfan, J / Dubois-Felsmann, G P / Dunwoodie, W / Field, R C / Gabareen, A M / Gowdy, S J / Graham, M T / Grenier, P / Hast, C / Innes, W R / Kaminski, J / Kelsey, M H / Kim, H / Kim, P / Kocian, M L / Leith, D W G S / Li, S / Lindquist, B / Luitz, S / Luth, V / Lynch, H L / MacFarlane, D B / Marsiske, H / Messner, R / Muller, D R / Neal, H / Nelson, S / O'Grady, C P / Ofte, I / Perazzo, A / Perl, M / Ratcliff, B N / Roodman, A / Salnikov, A A / Schindler, R H / Schwiening, J / Snyder, A / Su, D / sullivan, M K / Suzuki, K / Swain, S K / Thompson, J M / Va'vra, J / Wagner, A P / Weaver, M / West, C A / Wisniewski, W J / Wittgen, M / Wright, D H / Wulsin, H W / Yarritu, A K / Yi, K / Young, C C / Ziegler, V / Burchat, P R / Edwards, A J / Majewski, S A / Miyashita, T S / Petersen, B A / Wilden, L / Ahmed, S / Alam, M S / Ernst, J A / Pan, B / Saeed, M A / Zain, S B / Spanier, S M / Wogsland, B J / Eckmann, R / Ritchie, J L / Ruland, A M / Schilling, C J / Schwitters, R F / Drummond, B W / Izen, J M / Lou, X C / Bianchi, F / Gamba, D / Pelliccioni, M / Bomben, M / Bosisio, L / Cartaro, C / Della Ricca, G / Lanceri, L / Vitale, L / Azzolini, V / Lopez-March, N / Martinez-Vidal, F / Milanes, D A / Oyanguren, A / Albert, J / Banerjee, Sw / Bhuyan, B / Choi, H H F / Hamano, K / Kowalewski, R / Lewczuk, M J / Nugent, I M / Roney, J M / Sobie, R J / Gershon, T J / Harrison, P F / Ilic, J / Latham, T E / Mohanty, G B / Band, H R / Chen, X / Dasu, S / Flood, K T / Pan, Y / Pierini, M / Prepost, R / Vuosalo, C O / Wu, S L

Physical review letters

2008 Volume 101, Issue 26, Page(s) 261802

Abstract: We report a measurement of the branching fractions of B-->D**(l) nu(l), decays based on 417 fb(-1 ... We observe the B-->D**l(-1)nu(l) decay modes corresponding to the four D states predicted by heavy quark ... differences m(D(*) pi)- m(D(*)) is performed to extract the signal yields of the different D** states ...

Abstract	We report a measurement of the branching fractions of B-->D*(l) nu(l), decays based on 417 fb(-1) of data collected at the Y(4S) resonance with the BABAR detector at the PEP-II e+e- storage rings. Events are selected by full reconstructing one of the B mesons in a hadronic decay mode. A fit to the invariant mass differences m(D() pi)- m(D()) is performed to extract the signal yields of the different D* states. We observe the B-->D**l(-1)nu(l) decay modes corresponding to the four D states predicted by heavy quark symmetry with a significance greater than 5 standard deviations including systematic uncertainties.
Language	English
Publishing date	2008-12-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	208853-8
ISSN	1079-7114 ; 0031-9007
ISSN (online)	1079-7114
ISSN	0031-9007
DOI	10.1103/PhysRevLett.101.261802
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Article ; Online: La plainte de discrimination devant le Tribunal canadien des droits de la personne portant sur les services d’aide à l’enfance aux enfants des Premières Nations et le Principe de Jordan

Anne Levesque / Sarah Clarke / Cindy Blackstock

Enfances, Familles, Générations, Vol

2016 Volume 25

Abstract: More First Nations children today are being placed in foster care than the number of students who ever attended residential schools. It is becoming increasingly clear that this problem is caused by inequitable and insufficient federal government funding ... ...

Abstract	More First Nations children today are being placed in foster care than the number of students who ever attended residential schools. It is becoming increasingly clear that this problem is caused by inequitable and insufficient federal government funding for child welfare services. In 2007, the First Nations Child & Family Caring Society of Canada (the Caring Society) and the Assembly of First Nations filed a complaint concerning two allegations of discrimination. The first allegation concerned a conflict of jurisdiction between the federal and provincial governments that resulted in First Nations children often having to wait to receive vital services or even refused services provided to other children. The second allegation of discrimination concerned the unfair treatment of 163,000 First Nations children in the child welfare system provided on reserves. In both cases, it was alleged that these treatments constituted discriminatory acts prohibited under the Canada Human Rights Act. Over the next six years, the Canadian government spent millions of dollars on numerous unsuccessful attempts to derail the case. The case was nevertheless brought before the Human Rights Tribunal in February 2013; for the first time in Canadian history, the federal government’s liability regarding allegations of discrimination toward First Nations children was examined by a body that could make legally binding decisions and remedial orders. Over the year that followed, the Tribunal heard from over 25 witnesses and examined over 500 evidentiary documents. Internal federal documents that were submitted revealed consistent and systematic discrimination against First Nations children, along with a failure to resolve the problem, even with known solutions at hand. Even while the case was still before the Tribunal, a number of academics and members of First Nations began making parallels between the federal government’s reaction in this case and other cases of discrimination in access to services such as education, policing, health, ...
Keywords	First Nations ; children ; discrimination ; human rights ; Ethnology. Social and cultural anthropology ; GN301-674 ; The family. Marriage. Woman ; HQ1-2044
Subject code	320
Language	English
Publishing date	2016-10-01T00:00:00Z
Publisher	Centre Urbanisation Culture Société (UCS) de l'INRS
Document type	Article ; Online
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Article ; Online: GX15-070 (obatoclax) induces apoptosis and inhibits cathepsin D- and L-mediated autophagosomal lysis in antiestrogen-resistant breast cancer cells.

Schwartz-Roberts, Jessica L / Shajahan, Ayesha N / Cook, Katherine L / Wärri, Anni / Abu-Asab, Mones / Clarke, Robert

Molecular cancer therapeutics

2013 Volume 12, Issue 4, Page(s) 448–459

Abstract: ... in cathepsin D (CTSD) and L (CTSL1) protein expression that would otherwise digest autolysosome cargo ...

Abstract	In estrogen receptor-positive (ER+) breast cancer cells, BCL2 overexpression contributes to antiestrogen resistance. Direct targeting of the antiapoptotic BCL2 members with GX15-070 (obatoclax), a BH3-mimetic currently in clinical development, is an attractive strategy to overcome antiestrogen resistance in some breast cancers. Recently, GX15-070 has been shown to induce both apoptosis and autophagy, yet the underlying cell death mechanisms have yet to be elucidated. Here, we show that GX15-070 is more effective in reducing the cell density of antiestrogen-resistant breast cancer cells versus sensitive cells and that this increased sensitivity of resistant cells to GX15-070 correlates with an accumulation of autophagic vacuoles. Formation of autophagosomes in GX15-070-treated cells was verified by changes in expression of the lipidation of microtubule-associated protein-1 light chain-3 and both confocal and transmission electron microscopy. While GX15-070 treatment promotes autophagic vacuole and autolysosome formation, p62/SQSTM1, a marker for autophagic degradation, levels accumulate. Moreover, GX15-070 exposure leads to a reduction in cathepsin D (CTSD) and L (CTSL1) protein expression that would otherwise digest autolysosome cargo. Thus, GX15-070 has dual roles in promoting cell death: (i) directly inhibiting antiapoptotic BCL2 family members, thereby inducing apoptosis; and (ii) inhibiting downstream CTSD and CTSL1 protein expression to limit the ability of cells to use degraded material to fuel cellular metabolism and restore homeostasis. Our data highlight a new mechanism of GX15-070-induced cell death that could be used to design novel therapeutic interventions for antiestrogen resistant breast cancer.
MeSH term(s)	Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Apoptosis/drug effects ; Apoptosis Regulatory Proteins/metabolism ; Autophagy/drug effects ; Beclin-1 ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Cathepsin D/antagonists & inhibitors ; Cathepsin D/metabolism ; Cathepsin L/antagonists & inhibitors ; Cathepsin L/metabolism ; Cell Line, Tumor ; Drug Resistance, Neoplasm ; Estrogen Antagonists/pharmacology ; Female ; Humans ; Lysosomes/metabolism ; Membrane Proteins/metabolism ; Mice ; Microtubule-Associated Proteins/metabolism ; Phagosomes/metabolism ; Pyrroles/chemistry ; Pyrroles/pharmacology ; Pyrroles/toxicity ; Sequestosome-1 Protein ; Transplantation, Heterologous
Chemical Substances	Adaptor Proteins, Signal Transducing ; Apoptosis Regulatory Proteins ; BECN1 protein, human ; Beclin-1 ; Estrogen Antagonists ; MAP1LC3A protein, human ; Membrane Proteins ; Microtubule-Associated Proteins ; Pyrroles ; SQSTM1 protein, human ; Sequestosome-1 Protein ; Cathepsin L (EC 3.4.22.15) ; Cathepsin D (EC 3.4.23.5) ; obatoclax (QN4128B52A)
Language	English
Publishing date	2013-02-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-12-0617
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Article: Altered levels of S-adenosylmethionine and S-adenosylhomocysteine in the brains of L-isoaspartyl (D-Aspartyl) O-methyltransferase-deficient mice.

Farrar, Christine / Clarke, Steven

The Journal of biological chemistry

2002 Volume 277, Issue 31, Page(s) 27856–27863

Abstract: L-Isoaspartyl (D-aspartyl) O-methyltransferase (PCMT1) is a protein repair enzyme that initiates ... the conversion of abnormal D-aspartyl and L-isoaspartyl residues to the normal L-aspartyl form. In the course ...

Abstract	L-Isoaspartyl (D-aspartyl) O-methyltransferase (PCMT1) is a protein repair enzyme that initiates the conversion of abnormal D-aspartyl and L-isoaspartyl residues to the normal L-aspartyl form. In the course of this reaction, PCMT1 converts the methyl donor S-adenosylmethionine (AdoMet) to S-adenosylhomocysteine (AdoHcy). Due to the high level of activity of this enzyme, particularly in the brain, it seemed of interest to investigate whether the lack of PCMT1 activity might alter the concentrations of these small molecules. AdoMet and AdoHcy were measured in mice lacking PCMT1 (Pcmt1-/-), as well as in their heterozygous (Pcmt1+/-) and wild type (Pcmt1+/+) littermates. Higher levels of AdoMet and lower levels of AdoHcy were found in the brains of Pcmt1-/- mice, and to a lesser extent in Pcmt1+/- mice, when compared with Pcmt1+/+ mice. In addition, these levels appear to be most significantly altered in the hippocampus of the Pcmt1-/- mice. The changes in the AdoMet/AdoHcy ratio could not be attributed to increases in the activities of methionine adenosyltransferase II or S-adenosylhomocysteine hydrolase in the brain tissue of these mice. Because changes in the AdoMet/AdoHcy ratio could potentially alter the overall excitatory state of the brain, this effect may play a role in the progressive epilepsy seen in the Pcmt1-/- mice.
MeSH term(s)	Adenosylhomocysteinase ; Animals ; Aspartic Acid/metabolism ; Brain/metabolism ; Hydrolases/metabolism ; Kinetics ; Methionine Adenosyltransferase/metabolism ; Mice ; Mice, Knockout ; Protein D-Aspartate-L-Isoaspartate Methyltransferase/deficiency ; Protein D-Aspartate-L-Isoaspartate Methyltransferase/genetics ; Protein D-Aspartate-L-Isoaspartate Methyltransferase/metabolism ; S-Adenosylhomocysteine/metabolism ; S-Adenosylmethionine/metabolism ; Time Factors
Chemical Substances	Aspartic Acid (30KYC7MIAI) ; S-Adenosylmethionine (7LP2MPO46S) ; S-Adenosylhomocysteine (979-92-0) ; Protein D-Aspartate-L-Isoaspartate Methyltransferase (EC 2.1.1.77) ; Methionine Adenosyltransferase (EC 2.5.1.6) ; Hydrolases (EC 3.-) ; Adenosylhomocysteinase (EC 3.3.1.1)
Language	English
Publishing date	2002-05-22
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M203911200
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Article: Limited accumulation of damaged proteins in l-isoaspartyl (D-aspartyl) O-methyltransferase-deficient mice.

Lowenson, J D / Kim, E / Young, S G / Clarke, S

The Journal of biological chemistry

2001 Volume 276, Issue 23, Page(s) 20695–20702

Abstract: l-Isoaspartyl (d-aspartyl) O-methyltransferase (PCMT1) can initiate the conversion of damaged ... aspartyl and asparaginyl residues to normal l-aspartyl residues. Mice lacking this enzyme (Pcmt1-/- mice ...

Abstract	l-Isoaspartyl (d-aspartyl) O-methyltransferase (PCMT1) can initiate the conversion of damaged aspartyl and asparaginyl residues to normal l-aspartyl residues. Mice lacking this enzyme (Pcmt1-/- mice) have elevated levels of damaged residues and die at a mean age of 42 days from massive tonic-clonic seizures. To extend the lives of the knockout mice so that the long term effects of damaged residue accumulation could be investigated, we produced transgenic mice with a mouse Pcmt1 cDNA under the control of a neuron-specific promoter. Pcmt1 transgenic mice that were homozygous for the endogenous Pcmt1 knockout mutation ("transgenic Pcmt1-/- mice") had brain PCMT1 activity levels that were 6.5-13% those of wild-type mice but had little or no activity in other tissues. The transgenic Pcmt1-/- mice lived, on average, 5-fold longer than nontransgenic Pcmt1-/- mice and accumulated only half as many damaged aspartyl residues in their brain proteins. The concentration of damaged residues in heart, testis, and brain proteins in transgenic Pcmt1-/- mice initially increased with age but unexpectedly reached a plateau by 100 days of age. Urine from Pcmt1-/- mice contained increased amounts of peptides with damaged aspartyl residues, apparently enough to account for proteins that were not repaired intracellularly. In the absence of PCMT1, proteolysis may limit the intracellular accumulation of damaged proteins but less efficiently than in wild-type mice having PCMT1-mediated repair.
MeSH term(s)	Animals ; Aspartic Acid/metabolism ; Aspartic Acid/urine ; Base Sequence ; Brain/cytology ; Brain/enzymology ; DNA Primers ; Erythrocytes/metabolism ; Male ; Mice ; Mice, Transgenic ; Myocardium/metabolism ; Neurons/enzymology ; Promoter Regions, Genetic ; Protein D-Aspartate-L-Isoaspartate Methyltransferase ; Protein Methyltransferases/genetics ; Protein Methyltransferases/metabolism ; Testis/metabolism
Chemical Substances	DNA Primers ; Aspartic Acid (30KYC7MIAI) ; Protein Methyltransferases (EC 2.1.1.-) ; Protein D-Aspartate-L-Isoaspartate Methyltransferase (EC 2.1.1.77)
Language	English
Publishing date	2001-03-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M100987200
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Article: Family 39 alpha-l-iduronidases and beta-D-xylosidases react through similar glycosyl-enzyme intermediates: identification of the human iduronidase nucleophile.

Nieman, Catharine E / Wong, Alexander W / He, Shouming / Clarke, Lorne / Hopwood, John J / Withers, Stephen G

Biochemistry

2003 Volume 42, Issue 26, Page(s) 8054–8065

Abstract: The inclusion of both beta-D-xylosidases and alpha-L-iduronidases within the same sequence ... reveals that, as with the beta-D-xylosidases, alpha-L-iduronidase is a retaining glycosidase. Using two ... is one possibility. NMR analysis of the methanolysis reaction catalyzed by human alpha-L-iduronidase ...

Abstract	The inclusion of both beta-D-xylosidases and alpha-L-iduronidases within the same sequence-related family (family 39), despite the considerable difference in substrate structures and poor sequence conservation around the putative nucleophile, raises concerns about whether a common mechanism is followed by the two enzymes. A novel anchimeric assistance mechanism for iduronidases involving a lactone intermediate is one possibility. NMR analysis of the methanolysis reaction catalyzed by human alpha-L-iduronidase reveals that, as with the beta-D-xylosidases, alpha-L-iduronidase is a retaining glycosidase. Using two different mechanism-based inactivators, 5-fluoro-alpha-L-iduronyl fluoride and 2-deoxy-2-fluoro-alpha-L-iduronyl fluoride, the active site nucleophile in the human alpha-L-iduronidase was identified as Glu299 within the (295)IYNDEAD(301) sequence. The equivalent, though loosely predicted, glutamic acid was identified as the nucleophile in the family 39 beta-D-xylosidase from Bacillus sp. [Vocadlo, D., et al. (1998) Biochem. J. 335, 449-455]; thus, a common mechanism involving a covalent glycosyl-enzyme intermediate that adopts the rather uncommon (2,5)B conformation is predicted.
MeSH term(s)	Amino Acid Sequence ; Bacillus/enzymology ; Binding Sites ; Catalytic Domain ; Conserved Sequence ; Glutamic Acid/chemistry ; Humans ; Iduronic Acid/analogs & derivatives ; Iduronic Acid/chemical synthesis ; Iduronic Acid/metabolism ; Iduronidase/chemistry ; Iduronidase/metabolism ; Kinetics ; Mass Spectrometry/methods ; Molecular Sequence Data ; Peptide Fragments/chemistry ; Sequence Homology, Amino Acid ; Stereoisomerism ; Xylosidases/chemistry ; Xylosidases/metabolism
Chemical Substances	Peptide Fragments ; Iduronic Acid (3402-98-0) ; Glutamic Acid (3KX376GY7L) ; Xylosidases (EC 3.2.1.-) ; exo-1,4-beta-D-xylosidase (EC 3.2.1.37) ; Iduronidase (EC 3.2.1.76)
Language	English
Publishing date	2003-07-08
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/bi034293v
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Article: Polymorphic forms of the protein L-isoaspartate (D-aspartate) O-methyltransferase involved in the repair of age-damaged proteins.

DeVry, C G / Clarke, S

Journal of human genetics

1999 Volume 44, Issue 5, Page(s) 275–288

Abstract: The protein L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1) can initiate the repair of age ...

Abstract	The protein L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1) can initiate the repair of age-damaged aspartyl and asparaginyl residues of intracellular proteins. The human gene PCMT1 encoding this enzyme has at least four polymorphic sites, one of which results in two major isoforms with either an Ile residue or a Val residue at amino acid position 119. The frequencies of the alleles encoding the Ile119 and Val119 variants are similar in Caucasian populations, but a predominance of the Ile119 allele exists in Asian and African populations. Analyses of the enzymatic activities of the Ile119 and Val119 variants in red blood cell lysates show that the higher specific activity and thermostability of the Ile119 isoform is balanced by the potentially compensating higher substrate affinity of the Val119 isoform. In a preliminary attempt to find an association between genotype frequency at the PCMT1 locus and healthy aging, we compared the distribution of genotypes in a healthy older population of Ashkenazi Jewish individuals with that in a younger ethnically matched control group. We found that 65% of the healthy older population had the heterozygous genotype, greater than the 50% expected by Hardy-Weinberg equilibrium, suggesting a possible selection for having both alleles of the repair methyltransferase in successful aging. Three additional polymorphisms in noncoding regions of the methyltransferase gene were found to be biallelic and demonstrated nonrandom association in a specific haplotype with the codon 119 polymorphism. Finally, we also detected a heterozygous mutation in the splicing branch site of intron 2 that did not appear to affect activity. This study will help define the normal physiological range of activity for this repair methyltransferase and give us a better understanding of its role in the processes of aging and disease.
MeSH term(s)	African Continental Ancestry Group/genetics ; Aging ; Amino Acid Sequence ; Asian Continental Ancestry Group/genetics ; Base Sequence ; Consensus Sequence ; European Continental Ancestry Group/genetics ; Female ; Genetic Variation ; Humans ; Isoenzymes/genetics ; Isoenzymes/metabolism ; Isoleucine ; Jews/genetics ; Kinetics ; Korea ; Los Angeles ; Male ; Molecular Sequence Data ; Norway ; Pedigree ; Polymorphism, Genetic ; Protein D-Aspartate-L-Isoaspartate Methyltransferase ; Protein Methyltransferases/genetics ; Protein Methyltransferases/metabolism ; Substrate Specificity ; Valine
Chemical Substances	Isoenzymes ; Isoleucine (04Y7590D77) ; Protein Methyltransferases (EC 2.1.1.-) ; Protein D-Aspartate-L-Isoaspartate Methyltransferase (EC 2.1.1.77) ; Valine (HG18B9YRS7)
Language	English
Publishing date	1999
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	1425192-9
ISSN	1435-232X ; 1434-5161
ISSN (online)	1435-232X
ISSN	1434-5161
DOI	10.1007/s100380050161
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Article: Recognition of D-aspartyl residues in polypeptides by the erythrocyte L-isoaspartyl/D-aspartyl protein methyltransferase. Implications for the repair hypothesis.

Lowenson, J D / Clarke, S

The Journal of biological chemistry

1992 Volume 267, Issue 9, Page(s) 5985–5995

Abstract: ... for the L-isoaspartyl/D-aspartyl protein carboxyl methyltransferase (EC 2.1.1.77). We do this by showing ... by the lack of methylation of L-aspartyl-containing peptides under similar conditions. Methylation of D ... than are their L-isoaspartyl-containing counterparts. The physiological significance of D-aspartyl ...

Abstract	We provide here the first direct evidence that D-aspartyl residues in peptides are substrates for the L-isoaspartyl/D-aspartyl protein carboxyl methyltransferase (EC 2.1.1.77). We do this by showing that D-aspartic acid beta-methyl ester can be isolated from carboxypeptidase Y digests of enzymatically methylated D-aspartyl-containing synthetic peptides. The specificity of this reaction is supported by the lack of methylation of L-aspartyl-containing peptides under similar conditions. Methylation of D-aspartyl residues in synthetic peptides was not observed previously because with Km values ranging from 2.5 to 4.8 mM, these peptides are recognized by the methyltransferase with 700-10,000-fold lower affinity than are their L-isoaspartyl-containing counterparts. The physiological significance of D-aspartyl methylation was investigated in two ways. First, analysis of in situ methylated human erythrocyte proteins showed that at least 22% of the methyl groups associated with the proteins ankyrin and band 4.1 are on D-aspartyl residues, suggesting that D-aspartyl methylation is an important function of the methyltransferase in vivo. Second, mathematical modeling of the protein aging and methylation reactions occurring in intact erythrocytes indicated that the accumulation of D-aspartyl residues can be reduced as much as 2-5-fold by the methyltransferase activity. Although this reduction is much less than that predicted for L-isoaspartyl residues, it may be significant in maintaining functional proteins throughout the 120-day life span of these cells.
MeSH term(s)	Amino Acid Sequence ; Aspartic Acid ; Carboxypeptidases ; Erythrocyte Aging ; Erythrocytes/enzymology ; Humans ; Isomerism ; Kinetics ; Methylation ; Molecular Sequence Data ; Oligopeptides/chemical synthesis ; Peptide Fragments/isolation & purification ; Protein D-Aspartate-L-Isoaspartate Methyltransferase ; Protein Methyltransferases/blood ; Substrate Specificity
Chemical Substances	Oligopeptides ; Peptide Fragments ; Aspartic Acid (30KYC7MIAI) ; Protein Methyltransferases (EC 2.1.1.-) ; Protein D-Aspartate-L-Isoaspartate Methyltransferase (EC 2.1.1.77) ; Carboxypeptidases (EC 3.4.-) ; serine carboxypeptidase (EC 3.4.16.5)
Language	English
Publishing date	1992-03-25
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
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Article: Phenotypic analysis of seizure-prone mice lacking L-isoaspartate (D-aspartate) O-methyltransferase.

Kim, E / Lowenson, J D / Clarke, S / Young, S G

The Journal of biological chemistry

1999 Volume 274, Issue 29, Page(s) 20671–20678

Abstract: ... generating isomerized and racemized aspartyl residues. The enzyme protein L-isoaspartate (D-aspartate) O ... methyltransferase (E.C. 2.1.1.77) initiates the conversion of L-isoaspartyl and D-aspartyl residues to normal L ... Within proteins and peptides, both L-asparaginyl and L-aspartyl residues spontaneously degrade ...

Abstract	Within proteins and peptides, both L-asparaginyl and L-aspartyl residues spontaneously degrade, generating isomerized and racemized aspartyl residues. The enzyme protein L-isoaspartate (D-aspartate) O-methyltransferase (E.C. 2.1.1.77) initiates the conversion of L-isoaspartyl and D-aspartyl residues to normal L-aspartyl residues. This "repair" reaction helps to maintain proper protein conformation by preventing the accumulation of damaged proteins containing abnormal amino acid residues. Pcmt1-/- mice manifest two key phenotypes: a fatal seizure disorder and retarded growth. In this study, we characterized both phenotypes and demonstrated that they are linked. Continuous electroencephalogram monitoring of Pcmt1-/- mice revealed that abnormal cortical activity for approximately 50% of each 24-h period, even in mice that had no visible evidence of convulsions. The fatal seizure disorder in Pcmt1-/- mice can be mitigated but not eliminated by antiepileptic drugs. Interestingly, antiepileptic therapy normalized the growth of Pcmt1-/- mice, suggesting that the growth retardation is due to seizures rather than a global disturbance in growth at the cellular level. Consistent with this concept, the growth rate of Pcmt1-/- fibroblasts was indistinguishable from that of wild-type fibroblasts.
MeSH term(s)	Animals ; Anticonvulsants/pharmacology ; Anticonvulsants/therapeutic use ; Cell Division/genetics ; Dipeptides/metabolism ; Embryo, Mammalian/cytology ; Female ; Male ; Mice ; Mice, Knockout ; Phenotype ; Protein D-Aspartate-L-Isoaspartate Methyltransferase ; Protein Methyltransferases/genetics ; Protein Methyltransferases/metabolism ; Seizures/drug therapy ; Seizures/genetics ; Seizures/physiopathology ; Sexual Behavior, Animal/drug effects ; Substrate Specificity
Chemical Substances	Anticonvulsants ; Dipeptides ; isospaglumic acid (1W8M12WXYL) ; Protein Methyltransferases (EC 2.1.1.-) ; Protein D-Aspartate-L-Isoaspartate Methyltransferase (EC 2.1.1.77)
Language	English
Publishing date	1999-07-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.274.29.20671
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