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University of Groningen Exploring the mechanisms underlying the phenotype of MCAD deficiency with Systems Medicine Martines, Anne-Claire

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(1)University of Groningen. Exploring the mechanisms underlying the phenotype of MCAD deficiency with Systems Medicine Martines, Anne-Claire. IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.. Document Version Publisher's PDF, also known as Version of record. Publication date: 2019 Link to publication in University of Groningen/UMCG research database. Citation for published version (APA): Martines, A-C. (2019). Exploring the mechanisms underlying the phenotype of MCAD deficiency with Systems Medicine: from computational model to mice to man. Rijksuniversiteit Groningen.. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.. Download date: 28-06-2021.

(2) Chapter 5 Simulating the impact of genetic and environmental modifiers on MCAD deficiency in an extended computational model of human liver fatty-acid catabolism Anne-Claire M.F. Martines1,#, Dirk-Jan Reijngoud1,2, Barbara M. Bakkerƌϭ͕‫ۥ‬. 1 Laboratory. of Pediatrics, Center of Liver, Digestive and Metabolic Diseases, University of Groningen, Groningen, University Medical Center Groningen, Groningen, The Netherlands, 2 Department of Analytical Biochemistry, University of Groningen, Groningen, The Netherlands..

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(4) Simulating the impact of modifiers on MCAD deficiency in human liver fatty-acid catabolism. Abstract ‹–‘ Š‘†”‹ƒŽ ˆƒ––›Ǧƒ ‹† „‡–ƒǦ‘š‹†ƒ–‹‘ ȋ Ȍ ‹ –Š‡ Ž‹˜‡” ‹• ‘ˆ ”‹–‹ ƒŽ ‹’‘”–ƒ ‡ ˆ‘” ‡‡”‰›‡–ƒ„‘Ž‹•†—”‹‰ˆƒ•–‹‰ƒ†—†‡”‘–Š‡”‡‡”‰›Ǧ†‡ƒ†‹‰ ‘†‹–‹‘•ǤŠƒ’–‡”• ͵ ƒ† Ͷ Šƒ˜‡ •Š‘™ –Š‡ ‹’‘”–ƒ ‡ ‘ˆ •—””‘—†‹‰ ’ƒ–Š™ƒ›• ƒ† ’‡”‹’Š‡”ƒŽ –‹••—‡• ‘ Š‡’ƒ–‹  ˆ— –‹‘‹†‡ˆ‹ ‹‡ ›Ǥ

(5) –Š‹••–—†›ǡ™‡—•‡† ‘’—–ƒ–‹‘ƒŽ‘†‡Ž‹‰ –‘ ‰ƒ‹ ‘”‡‹•‹‰Š– ‹–‘ –Š‡”‘Ž‡ ‘ˆ –Š‡ •—””‘—†‹‰‡–™‘” ‘   ˆ— –‹‘ ‹  †‡ˆ‹ ‹‡ ›Ǥ ‘ –Š‹• ‡†ǡ ™‡ Š—ƒ‹œ‡† –Š‡ ”ƒ– †›ƒ‹  ‘†‡Ž ‘ˆ –Š‡   ’ƒ–Š™ƒ› ƒ† ‡š–‡†‡†‹–™‹–Š”‡Ž‡˜ƒ–’ƒ–Š™ƒ›•‘ˆ‡‡”‰›ƒ††‡–‘š‹ˆ‹ ƒ–‹‘‡–ƒ„‘Ž‹•ǤŠ‡•‹—Žƒ–‡† ˆŽ—š‡• ƒ† ‡–ƒ„‘Ž‹–‡ ’”‘ˆ‹Ž‡• ”‡ˆŽ‡ – –Š‡ ”‡Žƒ–‹˜‡ †‹•‡ƒ•‡ •‡˜‡”‹–‹‡• ‘ˆ ǡ ǡ ƒ†  †‡ˆ‹ ‹‡ › ‹ Š—ƒ•Ǥ —”–Š‡”‘”‡ǡ ™‡ •‹—Žƒ–‡† Šƒ‰‡• ‹ –Š‡ •—””‘—†‹‰ ‡–™‘”ǡ ‹ Ž—†‹‰ –Šƒ– ‘ˆ –Š‡ ˆ—–‹Ž‡ › Ž‡ ‘ˆ ƒ ›ŽǦ‘ Š›†”‘Ž›•‹• ƒ† ”‡ƒ –‹˜ƒ–‹‘Ǥ ‡’”‡••‹‘‘ˆ–Š‹• › Ž‡„›‘†—Žƒ–‹‰–Š‡•—„•–”ƒ–‡•’‡ ‹ˆ‹ ‹–›‘ˆͳǡ‹’ƒ‹”‡†–Š‡  ˆŽ—š‹–Š‡†‡ˆ‹ ‹‡–‘†‡Žǡ„—–Šƒ”†Ž›‹–Š‡‘”†‡ˆ‹ ‹‡–‘†‡Ž•ǤŠ‡•‡ ”‡•—Ž–• ‰‹˜‡ ƒ ˆ‹”•– ‹†‹ ƒ–‹‘ Š‘™ †‹ˆˆ‡”‡ ‡• ‹ ‰‡‡–‹  „ƒ ‰”‘—† ”‡Žƒ–‡† –‘ –Š‡ •—””‘—†‹‰’ƒ–Š™ƒ›• ‘—Ž†ƒˆˆ‡ ––Š‡˜—Ž‡”ƒ„‹Ž‹–›‘ˆ’ƒ–‹‡–•–‘‡–ƒ„‘Ž‹  ”‹•‹•Ǥ  . ͳͷͻ. 5.

(6) Chapter 5. Introduction ‹–‘ Š‘†”‹ƒŽˆƒ––›ƒ ‹†„‡–ƒǦ‘š‹†ƒ–‹‘ȋ Ȍ‹–Š‡Ž‹˜‡”‹•‘ˆ‡›‹’‘”–ƒ ‡ˆ‘”‡‡”‰› Š‘‡‘•–ƒ•‹•†—”‹‰ˆƒ•–‹‰‘” ‘†‹–‹‘•‘ˆŠ‹‰Š‡‡”‰›†‡ƒ†Ǥ

(7) –Š‡ ‡ŽŽǡˆƒ––›ƒ ‹†•ƒ”‡ ˆ‹”•–ƒ –‹˜ƒ–‡†„›ˆ‘”ƒ–‹‘‘ˆƒˆƒ––›Ǧƒ ‹†Ǧ ‘‡œ›‡ȋ‘Ȍ‡•–‡”ȋƒ ›ŽǦ‘Ȍ‹–Š‡ ›–‘•‘ŽǤ Š‡”‡•—Ž–‹‰ ›–‘•‘Ž‹ ƒ ›ŽǦ‘‡•–‡”•ƒ”‡–ƒ‡—’‹–‘–Š‡‹–‘ Š‘†”‹ƒƒ†‘š‹†‹œ‡†–‘ ƒ ‡–›ŽǦ‘ǡ ™Š‹ Š ‹• ˆ—”–Š‡” ‘š‹†‹œ‡† ‹ –Š‡ ‹–”‹  ƒ ‹† › Ž‡ ˆ‘” –Š‡ ˆ‘”ƒ–‹‘ ‘ˆ Ǥ

(8)  ƒ††‹–‹‘ǡ –Š‡ Ž‹˜‡” ƒ ‘˜‡”– ƒ ‡–›ŽǦ‘ –‘ ‡–‘‡ „‘†‹‡•ǡ ™Š‹ Š ƒ”‡ —•‡† „› ’‡”‹’Š‡”ƒŽ –‹••—‡•†—”‹‰ˆƒ•–‹‰ǡ–Š—••ƒ˜‹‰‰Ž— ‘•‡Ǥ Š‡ˆƒ––›Ǧƒ ‹†„‡–ƒǦ‘š‹†ƒ–‹‘•–ƒ”–•™‹–Š–Š‡–”ƒ•’‘”–‘ˆ–Š‡ƒ ›ŽǦ Šƒ‹‘ˆ ›–‘•‘Ž‹ ƒ ›ŽǦ‘ ‹–‘ ‹–‘ Š‘†”‹ƒ „› –Š‡ ƒ”‹–‹‡Ǧ•Š—––Ž‡ ȋFigure 1ǡ ™‹–Š –Š‡ •Š—––Ž‡ ‡œ›‡• ‰‹˜‡ ‹ ‰”‡‡ȌǤ Š‹••Š—––Ž‡ ‘’”‹•‡• –Š”‡‡ ‘•‡ —–‹˜‡ ”‡ƒ –‹‘•ǡ –”ƒ•ˆ‡” ‘ˆ –Š‡ ƒ ›Ž Šƒ‹ ˆ”‘ ƒ ›ŽǦ‘ ‘–‘ ƒ”‹–‹‡ ƒ–ƒŽ›œ‡† „› ƒ”‹–‹‡ ’ƒŽ‹–‘›Ž–”ƒ•ˆ‡”ƒ•‡ ȋȌͳǡ –”ƒ•’‘”– ‘ˆ ƒ ›ŽǦ ƒ”‹–‹‡ ƒ ”‘•• –Š‡ ‹–‘ Š‘†”‹ƒŽ ‹‡” ‡„”ƒ‡ ‹ ‡š Šƒ‰‡ ˆ‘” ƒ”‹–‹‡ „› ƒ”‹–‹‡ ƒ ›ŽǦ ƒ”‹–‹‡ –”ƒ•’‘”–‡” ȋȌǡ ƒ† –”ƒ•ˆ‡” ‘ˆ –Š‡ ƒ ›Ž Šƒ‹ ˆ”‘ ƒ ›ŽǦ ƒ”‹–‹‡ ‘–‘ ‘  „› ʹǤ ‡š– –Š‹• ƒ ›ŽǦ‘ ‹• •Š‘”–‡‡† ‹ ”‡’‡–‹–‹˜‡ ˆ‘—”Ǧ”‡ƒ –‹‘ › Ž‡•ǡ –Š‡”‡„› ’”‘†— ‹‰ ƒ ƒ ‡–›ŽǦ‘ ‘Ž‡ —Ž‡ ȏͳȂ͵Ȑ ‹ ‡ƒ Š › Ž‡Ǥ Š‡ ˆ‹”•– ”‡ƒ –‹‘‹ ‡ƒ Š › Ž‡‹• ƒ–ƒŽ›œ‡†„›ƒ•‡–‘ˆ‹•‘‡œ›‡•ǡ™Š‹ Šƒ ‡’–ƒ”ƒ‰‡‘ˆƒ ›ŽǦ‘•—„•–”ƒ–‡•‘ˆ †‹ˆˆ‡”‡–ǡ‘˜‡”Žƒ’’‹‰ ƒ”„‘Ǧ Šƒ‹Ž‡‰–Š•Ǥ

(9) Š—ƒ•ǡ–Š‡•‡ƒ”‡˜‡”›ǦŽ‘‰Ǧǡ‡†‹—Ǧǡƒ† •Š‘”–Ǧ Šƒ‹ƒ ›ŽǦ‘†‡Š›†”‘‰‡ƒ•‡ȋǡǡƒ†Ȍȏ͵ǡͶȐǤ

(10) –Š‹•”‡ƒ –‹‘ǡƒ ›ŽǦ ‘‹•†‡Š›†”‘‰‡ƒ–‡†ǡˆ‘”‹‰‡‘›ŽǦ‘ǡƒ† „‘—†‹–Š‡ƒ ›ŽǦ‘†‡Š›†”‘‰‡ƒ•‡ ‹•”‡†— ‡†–‘  ʹǤŠ‡”‡†— ‹‰‡“—‹˜ƒŽ‡–•ƒ”‡•—„•‡“—‡–Ž›–”ƒ•ˆ‡””‡†–‘–Š‡’”‘–‡‹ ‡Ž‡ –”‘ –”ƒ•ˆ‡” ˆŽƒ˜‘’”‘–‡‹ ȋ Ȍ ƒ† ˆ‹ƒŽŽ› –‘   †‡Š›†”‘‰‡ƒ•‡ ȋi.e.   —„‹“—‹‹‘‡ ‘š‹†‘”‡†— –ƒ•‡  Ȍ –”ƒ•ˆ‡”• –Š‡ ”‡†— ‹‰ ‡“—‹˜ƒŽ‡–• ˆ”‘  Ǧ„‘—†  ʹ–‘‘‹–Š‡‹–‘ Š‘†”‹ƒŽ‡Ž‡ –”‘–”ƒ•’‘”– Šƒ‹Ǥ

(11) –Š”‡‡ ‘•‡ —–‹˜‡”‡ƒ –‹‘•ǡ ‡‘›ŽǦ‘‹•Š›†”ƒ–‡†ǡƒ‰ƒ‹†‡Š›†”‘‰‡ƒ–‡†ǡ–Š‡”‡„›”‡†— ‹‰Ϊ–‘ ǡƒ†ˆ‹ƒŽŽ› –Š‹‘Ž›œ‡†Ǥ Š‡ –Š‹‘Žƒ•‡ ”‡ƒ –‹‘ ’”‘†— ‡• ƒ •Š‘”–‡‡† ƒ ›ŽǦ‘ ‡•–‡” ƒ† ƒ ‡–›ŽǦ‘ǡ ™‹–Š –Š‡ ‘ ‘‹–ƒ– ‘•—’–‹‘‘ˆƒˆ”‡‡‘‘Ž‡ —Ž‡ȋ”‡ˆ‡””‡†–‘ƒ•‘ ǡ„‡ ƒ—•‡‘ˆ‹–• ˆ”‡‡ –Š‹‘Ž ‰”‘—’ȌǤ Š‡ ’”‘†— –• ‘ˆ  ǡ ƒ ‡–›ŽǦ‘ǡ   ƒ† ƒ ›ŽǦ‘Ǧ†‡Š›†”‘‰‡ƒ•‡Ǧ „‘—†  ʹǡ ƒ„‡ˆ—”–Š‡”‘š‹†‹œ‡†–‘’”‘†— ‡‹–Š‡–”‹ ƒ”„‘š›Ž‹ ƒ ‹†ȋȌ › Ž‡ ƒ†‘š‹†ƒ–‹˜‡’Š‘•’Š‘”›Žƒ–‹‘ȋ ȌǤ—”‹‰ˆƒ•–‹‰‘”‹–‡•‡‡š‡” ‹•‡ǡ–Š‡Ž‹˜‡”—•‡• –Š‹•ˆ‘”–Š‡’”‘†— –‹‘‘ˆ‰Ž— ‘•‡„›‰Ž— ‘‡‘‰‡‡•‹•Ǥ

(12) „‘” †‡ˆ‹ ‹‡ ‹‡• ƒ••‘ ‹ƒ–‡† ™‹–Š Š—ƒ †‹•‡ƒ•‡ Šƒ˜‡ „‡‡ ‹†‡–‹ˆ‹‡† ˆ‘” ƒŽ‘•– ƒŽŽ –Š‡   ‡œ›‡•  ȏ͵ǡͷȐǤ †‡” ‡‡”‰›Ǧ†‡ƒ†‹‰ ‘†‹–‹‘•ǡ ‹†‹˜‹†—ƒŽ• ™‹–Š ƒ   †‡ˆ‹ ‹‡ › ”— ƒ ”‹• ‘ˆ •‡˜‡”‡ǡ Ž‹ˆ‡Ǧ–Š”‡ƒ–‡‹‰ Š›’‘‡–‘–‹  Š›’‘‰Ž› ‡‹ƒǤ ‹ ‡ –Š‡ ‹•‘‡œ›‡•ǡǡƒ†Šƒ˜‡‘˜‡”Žƒ’’‹‰•—„•–”ƒ–‡•’‡ ‹ˆ‹ ‹–‹‡•ȏ͵ǡͶȐǡ–Š‡› ƒ ‹ ’”‹ ‹’Ž‡ –ƒ‡ ‘˜‡” ‡ƒ Š ‘–Š‡”ǯ• ”‘Ž‡Ǥ Š‹• ƒ› ‡š’Žƒ‹ ™Š› Ǧ†‡ˆ‹ ‹‡– ȋȌ Š‹Ž†”‡‘ˆ–‡Šƒ˜‡‘Ž›‹‘”•›’–‘•ȏ͸ȐǤŠ‡†‹•‡ƒ•‡’”‡•‡–ƒ–‹‘‰‡‡”ƒŽŽ›„‡ ‘‡• ‘”‡•‡˜‡”‡ˆ”‘–‘–‘ȏ͵ȐǤ ‘™‡˜‡”ǡ–Š‡”‡‹•ƒŽƒ”‰‡Š‡–‡”‘‰‡‡‹–› ‹ †‹•‡ƒ•‡ ’”‡•‡–ƒ–‹‘ „‡–™‡‡  Ǧ†‡ˆ‹ ‹‡– ȋ Ȍ ‹†‹˜‹†—ƒŽ• ™‹–Š –Š‡ •ƒ‡ ‡œ›‡ †‡ˆ‹ ‹‡ ›ǡ ƒ† ‡˜‡ ™‹–Š –Š‡ •ƒ‡ ‰‡‡–‹  —–ƒ–‹‘Ǥ ‘” ‡šƒ’Ž‡ǡ ƒ •—„•‡– ‘ˆ Š‹Ž†”‡™‹–ŠƒŠ‘‘œ›‰‘—•Ž‘••Ǧ‘ˆǦˆ— –‹‘ Ǥͻͺͷε —–ƒ–‹‘‹–Š‡ACADM‰‡‡ǡ™Š‹ Š ‡ ‘†‡• ǡ ƒ ’”‡•‡– ™‹–Š Ž‹ˆ‡Ǧ–Š”‡ƒ–‡‹‰ Š›’‘‰Ž› ‡‹ƒȏ͵ǡͷȐǡ ™Š‹Ž‡ ƒ †‹ˆˆ‡”‡– •—„•‡– ‘ˆ –Š‡•‡ Š‹Ž†”‡ ‡˜‡” †‡˜‡Ž‘’• ƒ› •›’–‘• ȏ͹ȂͳͷȐǤ

(13) – ™ƒ• ”‡’‘”–‡† –Šƒ– ‹†‹˜‹†—ƒŽ• Š‘‘œ›‰‘—• ˆ‘” –Š‡ Ǥͻͺͷε  —–ƒ–‹‘ ƒ”‡ ƒ„Ž‡ –‘ ˆƒ•– ˆ‘” ͳͺǦʹͶ Š‘—”• ȏ͵ǡ͹ǡͳ͸ǡͳ͹ȐǤ ‘„‹ƒ–‹‘‘ˆ’”‘Ž‘‰‡†ˆƒ•–‹‰ƒ†ƒƒ††‹–‹‘ƒŽ–”‹‰‰‡”ǡ•— Šƒ•ƒƒ‹”™ƒ› ͳ͸Ͳ.

(14) Simulating the impact of modifiers on MCAD deficiency in human liver fatty-acid catabolism ‘”‰ƒ•–”‘‹–‡•–‹ƒŽ‹ˆ‡ –‹‘ǡƒŽ ‘Š‘Ž—•‡ǡ‘” ‘Ž†Ǧ‡š’‘•—”‡ǡ‹ ”‡ƒ•‡•–Š‡”‹•‘ˆŠ›’‘‡–‘–‹  Š›’‘‰Ž› ‡‹ƒȏͷǡͳͷǡͳͺȂʹͲȐǤ ‘ ‹˜‡•–‹‰ƒ–‡ –Š‡ „‹‘ Š‡‹ ƒŽ „ƒ•‹• ˆ‘” –Š‡ †‹ˆˆ‡”‡ ‡ ‹ ‡–ƒ„‘Ž‹  ”‘„—•–‡•• „‡–™‡‡ ‹†‹˜‹†—ƒŽ•ǡ ™‡ Šƒ˜‡ ‘•–”— –‡† ƒ †›ƒ‹  ‘’—–ƒ–‹‘ƒŽ ‘†‡Ž ‘ˆ –Š‡  ʹ͸Ǥ ‘†‡Ž •‹—Žƒ–‹‘•”‡˜‡ƒŽ‡†ƒ’‘–‡–‹ƒŽ˜‹ ‹‘—• › Ž‡‘ˆ‘‡•–‡”ƒ ——Žƒ–‹‘ǡ‘ †‡’Ž‡–‹‘ǡ ƒ†   ˆŽ—š †‡ Ž‹‡ ȏʹͳȐǡ ™Š‹ Š ™ƒ• ƒ—•‡† „› ƒ Š‹‰Š ‘ ‡–”ƒ–‹‘ ‘ˆ –Š‡ •—„•–”ƒ–‡ ’ƒŽ‹–‘›ŽǦ‘ ƒ† ƒ‰‰”ƒ˜ƒ–‡† „› Ž‘•• ‘ˆ  ȏͶȐǤ Š‡ ‘ Ǧ ‘•—‹‰ ‡œ›‡ ‘ˆ –Š‡ Žƒ•–   ”‡ƒ –‹‘ǡ ‡†‹—Ǧ Šƒ‹ ‡–‘ƒ ›ŽǦ‘ –Š‹‘Žƒ•‡ ȋȌƒ† –Š‡ ΪǦ”‡†— ‹‰ ‡œ›‡ ‡†‹—Ǧ Šƒ‹ Š›†”‘š›ƒ ›ŽǦ‘ †‡Š›†”‘‰‡ƒ•‡ ȋ Ȍ ’Žƒ›‡† ƒ ‹’‘”–ƒ– ”‘Ž‡ ‹ –Š‡ —†‡”Ž›‹‰‡ Šƒ‹• ȏʹͳȐ ȋChapter 2ȌǤ Š‡ ‘†‡Ž ™ƒ• „ƒ•‡†‘ „‹‘ Š‡‹ ƒŽ †ƒ–ƒ–Šƒ–Šƒ†„‡‡ ‘ŽŽ‡ –‡†‘•–Ž›ˆ”‘”ƒ–‹–‘ Š‘†”‹ƒǤŠ—ƒ˜‡”•‹‘‘ˆ–Š‡‘†‡Ž Šƒ• „‡‡ †‡”‹˜‡† „› ˆ‹––‹‰ ‘ˆ ƒ •—„•‡– ‘ˆ ‘†‡Ž ’ƒ”ƒ‡–‡”• –‘ ’Žƒ•ƒ ƒ ›ŽǦ ƒ”‹–‹‡• ‘ˆ Š‡ƒŽ–Š›‹†‹˜‹†—ƒŽ•ȏʹʹȐǤŠ‹•Š—ƒ‘†‡Ž˜‡”•‹‘ ‘—Ž†‡š’Žƒ‹–Š‡†‹ˆˆ‡”‡ ‡‹•‡˜‡”‹–› ‘ˆ †‹•‡ƒ•‡ ’”‡•‡–ƒ–‹‘ „‡–™‡‡ –™‘ ‹†‹˜‹†—ƒŽ• ™‹–Š —Ž–‹’Ž‡Ǧƒ ›ŽǦ‘ †‡Š›†”‘‰‡ƒ•‡ †‡ˆ‹ ‹‡ ›ȋȌǡƒ ‘†‹–‹‘ ƒ—•‡†„›ƒ†‡ˆ‡ –‹ ‘” †‡Š›†”‘‰‡ƒ•‡ȏʹʹȐǤŠ‡ ‘†‡ŽŠƒ•Š‘™‡˜‡”ǡ‘–›‡–„‡‡ƒ’’Ž‹‡†–‘‹˜‡•–‹‰ƒ–‡Š‡–‡”‘‰‡‡‘—•†‹•‡ƒ•‡’”‡•‡–ƒ–‹‘ ‘ˆ‘–Š‡”‡œ›‡†‡ˆ‡ –•Ǥ ‘–‡–‹ƒŽŽ›ǡ•—„–Ž‡†‹ˆˆ‡”‡ ‡•‹‰‡‡–‹ „ƒ ‰”‘—† ‡š’Žƒ‹†‹ˆˆ‡”‡ ‡•‹˜—Ž‡”ƒ„‹Ž‹–›‘ˆ ”‘„—•–‡••‘ˆ ’ƒ–‹‡–•ǤŠ‹•ƒ›„‡”‡Žƒ–‡†–‘†‹ˆˆ‡”‡ ‡•™‹–Š‹–Š‡ ’ƒ–Š™ƒ›ǡ ‡Ǥ‰Ǥ†—‡–‘†‹ˆˆ‡”‡ ‡•‹ ‘ ‡–”ƒ–‹‘•‘”ƒ –‹˜‹–›‘ˆ–Š‡”‡ƒ‹‹‰‡œ›‡•Ǥ ‘™‡˜‡”ǡ–Š‡ ‘ˆƒ –‘”• Ϊ ƒ† ‘  ƒ˜ƒ‹Žƒ„‹Ž‹–› ƒŽ•‘ ’Žƒ›• ƒ ”‹–‹ ƒŽ ”‘Ž‡ ‹  Ǥ Š‡”‡ˆ‘”‡ǡ ™‡ Ž‘‘‡†‹–‘–Š‡‹–”‹ ƒ–‡ ‘‡ –‹‘‘ˆ–Š‡ ’ƒ–Š™ƒ›™‹–Š‘–Š‡”‡–ƒ„‘Ž‹ ’ƒ–Š™ƒ›•‘ˆ ‡–ƒ„‘Ž‹•ǡ’ƒ”–‹ —Žƒ”Ž›–Š‘•‡‹™Š‹ Š–Š‡•‡ ‘ˆƒ –‘”•ƒ”‡‹˜‘Ž˜‡†Ǥ‹ ‡ƒŠ‹‰Š ˆŽ—š ”‡“—‹”‡• Š‹‰Š ‘ ‡–”ƒ–‹‘• ‘ˆ Ϊ ƒ† ‘ ǡ ™‡ Š›’‘–Š‡•‹œ‡ –Šƒ– ’ƒ–Š™ƒ›• –Šƒ– ‹ ”‡ƒ•‡ –Š‡•‡ ‘ ‡–”ƒ–‹‘•ǡ ƒ› ƒŽŽ‡˜‹ƒ–‡ Ž‹‹ ƒŽ •›’–‘•Ǥ

(15)  ‘–”ƒ•–ǡ ’ƒ–Š™ƒ›• –Šƒ– †‡ ”‡ƒ•‡Ϊ‘”‘ ǡƒ›ƒ‰‰”ƒ˜ƒ–‡–Š‡”‹•‘ˆƒ‡–ƒ„‘Ž‹  ”‹•‹•Ǥ Š‡’ƒ–Š™ƒ›•–Šƒ–—–‹Ž‹œ‡–Š‡’”‘†— –•‘ˆ ƒ”‡–›’‹ ƒŽŽ›‹–Š‡ ƒ–‡‰‘”›‘ˆƒŽŽ‡˜‹ƒ–‹‰ ’ƒ–Š™ƒ›•Ǥ

(16)  –Š‹• ƒ–‡‰‘”›ǡ ‡–‘‰‡‡•‹• ‹• –Š‡ ’”‘†— –‹‘ ‘ˆ –Š‡ ‡–‘‡ „‘†‹‡• EǦŠ›†”‘š›Ǧ „—–›”ƒ–‡ƒ†ƒ ‡–‘ƒ ‡–ƒ–‡‹–Š‡Ž‹˜‡”ȋFigure 1ȌǤŠ‡•‡‡–‘‡„‘†‹‡•ƒ”‡•‡ ”‡–‡†‹–‘–Š‡ ’Žƒ•ƒ ˆ‘” ‘•—’–‹‘ ƒ• ˆ—‡Ž „› ’‡”‹’Š‡”ƒŽ –‹••—‡• ƒ† „”ƒ‹Ǥ Š‡ ‡–‘‰‡‡•‹• ’ƒ–Š™ƒ› —•‡• ƒ ‡–›ŽǦ‘ ƒ† ƒ ‡–‘ƒ ‡–›ŽǦ‘ ȋͶǦ‡–‘ƒ ›ŽǦ‘Ȍ ƒ• •—„•–”ƒ–‡• ƒ† ”‡‰‡‡”ƒ–‡• ‘ Ǥ

(17)  –Š‡ ‘˜‡”•‹‘ ‘ˆ ƒ ‡–‘ƒ ‡–ƒ–‡ –‘ EǦŠ›†”‘š›Ǧ„—–›”ƒ–‡ ȋ”‘—‰ŠŽ› ʹͷǦͶͺΨ ‘ˆ –Š‡ –‘–ƒŽ ‡–‘‡Ǧ„‘†› ’‘‘Ž ȏʹ͵ǡʹͶȐȌǡ   ‹•”‡‘š‹†‹œ‡† ‹–‘ ΪǤ › ‹ ”‡ƒ•‹‰ „‘–Š ‘  ƒ† Ϊǡ –Š‡ ‡–‘‰‡‡•‹• ’ƒ–Š™ƒ› •Š‘—Ž† •–‹—Žƒ–‡ –Š‡   ˆŽ—šǤ ‡ ‘†ǡ –Š‡   •›•–‡ ‹• –Š‡ ƒŒ‘” Ǧ’”‘†— ‹‰ •›•–‡ –Šƒ– ”‡‘š‹†‹œ‡•   –‘ Ϊ ƒ† ’”‘–‡‹Ǧ „‘—†  ʹ –‘ ΪǤ  ƒ –‹˜‡   ’ƒ–Š™ƒ› ™‘—Ž† –Š‡”‡ˆ‘”‡ •–‹—Žƒ–‡ –Š‡  Ǥ ‡ ‡–Ž›ǡ Š‘™‡˜‡”ǡ ‹– ™ƒ• ”‡’‘”–‡† –Šƒ– –Š‡   •›•–‡ ˆ— –‹‘• •—„‘’–‹ƒŽŽ› ‹ ˆ‹„”‘„Žƒ•–•‘ˆ  ’ƒ–‹‡–• ȏʹͷȐǡ ™Š‹ Š ‹‰Š– ƒ‰‰”ƒ˜ƒ–‡ –Š‡‹” Ž‹‹ ƒŽ •›’–‘• ȏͶǡʹ͸ȐǤ Š‹”†ǡ –Š‡ ‡š’‘”– ‘ˆ ƒ ›ŽǦ ƒ”‹–‹‡• ƒ ”‡Ž‹‡˜‡ –Š‡ ‹–‘ Š‘†”‹ƒ ˆ”‘ ƒ ——Žƒ–‹‰ ‘ ‡•–‡”• ƒ† –Š‡”‡„› Ž‹„‡”ƒ–‡ ‘ Ǥ ‹ƒŽŽ›ǡ –Š‡ Š›†”‘Ž›•‹• ‘ˆ ƒ ›ŽǦ‘ ‡•–‡”• „› ‹–‘ Š‘†”‹ƒŽ ƒ ›ŽǦ‘ –Š‹‘‡•–‡”ƒ•‡• ȋȌ ”‡Ž‡ƒ•‡• ‘  ƒ† ƒ› –Š‡”‡„› •–‹—Žƒ–‡ –Š‡ ǤŠ‡”‡•—Ž–‹‰ˆ”‡‡ˆƒ––›ƒ ‹†•ȋ •Ȍƒ›„‡•‡ ”‡–‡†ƒ†”‡ƒ –‹˜ƒ–‡†„› ›–‘•‘Ž‹  ƒ ›ŽǦ‘ •›–Š‡–ƒ•‡• ȋ•Ȍ ȋFigure 1ȌǤ Š‹• ˆ—–‹Ž‡ › Ž‡ Šƒ• ‹†‡‡† „‡‡ ”‡’‘”–‡† –‘ ‘–”‹„—–‡ –‘ –Š‡   ˆŽ—š  ȏʹ͹Ȃ͵ͲȐ ƒ† ƒ› –Š‡”‡ˆ‘”‡ ƒŽŽ‡˜‹ƒ–‡ †‹•‡ƒ•‡ •›’–‘•Ǥ Š‡ ˆ‹ƒŽ ƒŽŽ‡˜‹ƒ–‹‰ ’ƒ–Š™ƒ› ™‘—Ž† „‡ –Š‡ ‹ ”‘•‘ƒŽ ɘǦ‘š‹†ƒ–‹‘ ’ƒ–Š™ƒ›ǡ ™Š‹ Š ‘š‹†‹œ‡• ͳ͸ͳ. 5.

(18) Chapter 5 ‡†‹—Ǧ Šƒ‹ˆƒ––›ƒ ‹†•–‘–Š‡‹” ‘””‡•’‘†‹‰†‹ ƒ”„‘š›Ž‹ ƒ ‹†•ǤŠ‹•’ƒ–Š™ƒ›™‘—Ž†„‡ ƒ •‹ ˆ‘” ‡†‹—Ǧ Šƒ‹ ƒ ›ŽǦ‘ ‡•–‡”• –Šƒ– –‡† –‘ ƒ ——Žƒ–‡ ™Š‡  ‹• †‡ˆ‹ ‹‡–Ǥ

(19) †‡‡†ǡ‹†‹˜‹†—ƒŽ••Š‘™Š‹‰Š‡”‡†‹—Ǧ Šƒ‹†‹ ƒ”„‘š›Ž‹ ƒ ‹†Ž‡˜‡Ž•‹„Ž‘‘†ƒ† —”‹‡ ‘’ƒ”‡† –‘ —ƒˆˆ‡ –‡† ‹†‹˜‹†—ƒŽ•ǡ ‹†‹ ƒ–‹‰ –Šƒ– –Š‡ ‘‡‰ƒǦ‘š‹†ƒ–‹‘ ƒ „‡ ‘•‹†‡”‡†ƒ’‘–‡–‹ƒŽ”‡• —‡’ƒ–Š™ƒ›‹ ȏ͵ͳȐǤ ‘”†‹‰–‘‘—””ƒ–‹‘ƒŽ‡ǡ’”‘ ‡••‡• –Šƒ– ‘’‡–‡ˆ‘”–Š‡ƒ˜ƒ‹Žƒ„Ž‡‘ ‘”Ϊ™‘—Ž†‹Š‹„‹––Š‡ ƒ†ƒ›ƒ‰‰”ƒ˜ƒ–‡ –Š‡”‹•‘ˆ Ž‹‹ ƒŽ•›’–‘•ȏ͵ʹǡ͵͵ȐǤ‹—Ž–ƒ‡‘—•‘š‹†ƒ–‹‘‘ˆ—Ž–‹’Ž‡•—„•–”ƒ–‡•™‘—Ž† „‡ ‹ –Š‹• ƒ–‡‰‘”›Ǥ —”‹‰ ˆƒ•–‹‰ǡ ‘š‹†ƒ–‹‘ ‘ˆ ‰Ž— ‘•‡ •Š‘—Ž† „‡ ‹‹ƒŽǤ ”‡ƒ†‘™ ‘ˆ ’”‘–‡‹•ǡŠ‘™‡˜‡”ǡ™‘—Ž†’”‘†— ‡Š‹‰Š‡”Ž‡˜‡Ž•‘ˆƒ‹‘ƒ ‹†•Ǥƒ”–‹ —Žƒ”Ž›–Š‡ ƒ–ƒ„‘Ž‹• ‘ˆ „”ƒ Š‡†Ǧ Šƒ‹ ƒ‹‘ ƒ ‹†• ”‡“—‹”‡• ‘ Ǥ

(20)  ƒ††‹–‹‘ǡ ƒ–ƒ„‘Ž‹• ‘ˆ š‡‘„‹‘–‹ • ”‡“—‹”‡•‘ Ǥ Š‡ ƒ‹ ‘ˆ –Š‹• •–—†› ™ƒ• –‘ ‡š’Ž‘”‡ –Š‡ ‹’ƒ – ‘ˆ ’‘–‡–‹ƒŽ ƒŽŽ‡˜‹ƒ–‹‰ ’ƒ–Š™ƒ›• ‘ –Š‡ Š‡’ƒ–‹    ˆŽ—šǡ ‹ ‘”†‡” –‘ ‰ƒ‹ ‹•‹‰Š– ‹–‘ ‡ Šƒ‹•• —†‡”Ž›‹‰ –Š‡ †‹•‡ƒ•‡ ’”‡•‡–ƒ–‹‘‘ˆǡƒ†Ǥ‘–Š‹•‡†ǡ™‡”‡˜‹•‹–‡†–Š‡ ‘˜‡”•‹‘‘ˆ–Š‡ ”ƒ–   ‘†‡Ž ‹–‘ ƒ Š—ƒ ˜‡”•‹‘ǡ ƒ† ‡š–‡†‡† ‹– ™‹–Š –Š‡ ƒŽŽ‡˜‹ƒ–‹‰ ’ƒ–Š™ƒ›• †‹• —••‡† ƒ„‘˜‡Ǥ ‘Ǧ ƒ–ƒ„‘Ž‹• ‘ˆ ‘’‡–‹‰ •—„•–”ƒ–‡• ‹• ‘– ’ƒ”– ‘ˆ –Š‹• •–—†›Ǥ

(21)  –Š‡ ‡š–‡†‡† ‘†‡Ž ™‡ •‹—Žƒ–‡† †‡ˆ‹ ‹‡ ‹‡• ‘ˆ –Š‡ †‹ˆˆ‡”‡– ƒ ›ŽǦ‘ †‡Š›†”‘‰‡ƒ•‡• ȋ•Ȍ ƒ† ƒ†‡ •—„–Ž‡ ˜ƒ”‹ƒ–‹‘• ‹ ‘ˆƒ –‘” ƒ˜ƒ‹Žƒ„‹Ž‹–‹‡• ‘” ƒ –‹˜‹–‹‡• ‘ˆ –Š‡ ƒ††‡† ’ƒ–Š™ƒ›•Ǥ‡•Š‘™–Šƒ––Š‡‘†‡Ž”‡’”‘†— ‡• –Š‡†‹ˆˆ‡”‡ ‡•‹†‹•‡ƒ•‡•‡˜‡”‹–›–Šƒ–ƒ”‡ ‰‡‡”ƒŽŽ› ‘„•‡”˜‡† „‡–™‡‡ ǡ ǡ ƒ†  ’ƒ–‹‡–•Ǥ

(22)  ƒ††‹–‹‘ǡ –Š‡ •‹—Žƒ–‡†‹–‡”˜‡–‹‘••Š‘™–Šƒ–†‹ˆˆ‡”‡ ‡•‹ ‘ˆƒ –‘”ƒ˜ƒ‹Žƒ„‹Ž‹–›ƒ†‡œ›‡ƒ –‹˜‹–‹‡• ƒ›‰‹˜‡”‹•‡–‘†‹ˆˆ‡”‡–ˆŽ—š‡•‹’ƒ–‹‡–•™‹–Š–Š‡•ƒ‡—–ƒ–‹‘Ǥ‡™‹ŽŽ†‹• —••Š‘™–Š‡ ‘†‡Ž ƒ› „‡ —•‡† ƒ• ƒ •–ƒ”–‹‰ ’‘‹– –‘ ‹˜‡•–‹‰ƒ–‡ –Š‡ †‹ˆˆ‡”‡ ‡• ‹ Ž‹‹ ƒŽ •›’–‘• „‡–™‡‡‹†‹˜‹†—ƒŽ’ƒ–‹‡–•Ǥ . Results Model construction and characterization •ƒ•–ƒ”–‹‰’‘‹–ˆ‘”‘†‡Ž‡š–‡•‹‘™‡ˆ‹”•– ‘•‹†‡”‡†–Š‡’”‡˜‹‘—•Ž›’—„Ž‹•Š‡†Š—ƒ ˜‡”•‹‘ ‘ˆ –Š‡   ‘†‡Ž ȏʹʹȐǤ Š‡ ™‡ •‹—Žƒ–‡†  †‡ˆ‹ ‹‡ › ‹ –Š‹• ‘†‡Žǡ ‘ †‹ˆˆ‡”‡ ‡‹ ˆŽ—š™ƒ•‘„•‡”˜‡†„‡–™‡‡–Š‡‘ ‘—–ȋȌƒ†‘†‡Žƒ– ƒ‹ ”‡ƒ•‹‰ ‘ ‡–”ƒ–‹‘‘ˆ–Š‡•—„•–”ƒ–‡’ƒŽ‹–‘›ŽǦ‘ȋͳ͸Ǧƒ ›ŽǦ‘Ȍȋ—’’Ž‡‡–ƒ”› ˆ‹‰—”‡ͳȌǤ

(23) –Š‡‘†‡Ž ƒ””‹‡†Ž‹––Ž‡ˆŽ—šȋ—’’Ž‡‡–ƒ”› ‹‰—”‡ͳȌǤ‡†‘—„– –Šƒ– –Š‹•‹•”‡ƒŽ‹•–‹ Ǥ

(24) – ‹‰Š– ”ƒ–Š‡” „‡ ƒƒ”–‹ˆƒ – ‘ˆ ’ƒ”ƒ‡–‡” ˆ‹––‹‰™Š‡ –Š‡ ”ƒ– ‘†‡Ž ™ƒ• ‘˜‡”–‡†‹–‘ƒŠ—ƒ˜‡”•‹‘ȏʹʹȐǤŠ‡”‡ˆ‘”‡ǡ™‡™‡–„ƒ –‘–Š‡‘”‹‰‹ƒŽ”ƒ–‘†‡Žǡ ™Š‹ Š ™ƒ• „ƒ•‡† ‘ ’”‹ƒ”› ‡œ›‡ ‹‡–‹  †ƒ–ƒǤ Š‡”‡ ’‘••‹„Ž‡ǡ ’ƒ”ƒ‡–‡”• ™‡”‡ ”‡’Žƒ ‡†„›˜ƒŽ—‡•†‹”‡ –Ž›‡ƒ•—”‡†‘Š—ƒ‡œ›‡•ǤŠ‡Ž‘‰Ǧ Šƒ‹ƒ ›ŽǦ‘ȋȌ ‹•‘‡œ›‡™ƒ•”‡‘˜‡†ǡ•‹ ‡‹–‹•‘–‡š’”‡••‡†‹Š—ƒŽ‹˜‡”ȏ͵ͶȐǤ‡š–ǡ–Š‡‘†‡Ž™ƒ• ‡š’ƒ†‡†™‹–Š–Š‡’ƒ–Š™ƒ›•†‡’‹ –‡†‹ ‹‰—”‡ͳǡ‘–ƒ„Ž›‡–‘‰‡‡•‹•ǡ †‡Š›†”‘‰‡ƒ•‡ǡ ‹–‘ Š‘†”‹ƒŽ ǡ ›–‘•‘Ž‹   ”‡ƒ –‹˜ƒ–‹‘ „› ǡ ƒ† ‹ ”‘•‘ƒŽ ‘‡‰ƒǦ‘š‹†ƒ–‹‘Ǥ —”–Š‡”‘”‡ǡ –Š‡ ‡š’‘”– ‘ˆ ƒ ›ŽǦ ƒ”‹–‹‡•ǡ • ƒ† †‹ ƒ”„‘š›Ž‹  ƒ ‹†• ȋ•Ȍ ‘—– ‘ˆ –Š‡ ‡ŽŽ™‡”‡‹ ‘”’‘”ƒ–‡†Ǥ ‘”–Š‡‡–‘‰‡‡•‹•’ƒ–Š™ƒ›ǡƒŽŽ”‡ƒ –‹‘•™‡”‡‹ Ž—†‡†ǡ•‹ ‡–Š‡› †‹”‡ –Ž› ‹˜‘Ž˜‡ ‘ –Š‹‘‡•–‡”•ǡ ‘  ƒ† ΪǤ ‘” –Š‡   †‡Š›†”‘‰‡ƒ•‡Ǧ ƒ–ƒŽ›œ‡† ”‡ƒ –‹‘ǡ ǡ‘ƒ†‹–•”‡†— ‡† ‡“—‹˜ƒŽ‡–ȋ‘ ʹȌ™‡”‡‹ Ž—†‡†Ǥ‘”‡ › Ž‡ ›–‘•‘Ž‹  ƒ ›ŽǦ‘‡•–‡”•‰‡‡”ƒ–‡†„›‹–‘–Š‡ ǡ–Š‡‹‡–‹ •‘ˆͳŠƒ†–‘„‡ƒ†ƒ’–‡†Ǥ

(25)  ’”‡˜‹‘—•‘†‡Ž˜‡”•‹‘•‹–•‘Ž›•—„•–”ƒ–‡™ƒ•’ƒŽ‹–‘›ŽǦ‘ǡ„—–‹”‡ƒŽ‹–›‹–ƒŽ•‘ ‘˜‡”–• ͳ͸ʹ.

(26) Simulating the impact of modifiers on MCAD deficiency in human liver fatty-acid catabolism ‘–Š‡” ƒ ›ŽǦ‘ ‡•–‡”• –‘ ƒ ›ŽǦ ƒ”‹–‹‡• ȏ͵ͷȐǤ Š‡ ‘‡‰ƒǦ‘š‹†ƒ–‹‘ ™ƒ• ”‡’”‡•‡–‡† „› ƒ •‹‰Ž‡ ”‡ƒ –‹‘ǡ ˆ‘” ™Š‹ Š –Š‡ ‹‡–‹ • ‘ˆ Ͷͳͳ ȏ͵͸Ȑ ™‡”‡ —•‡†Ǥ  ƒ–Š‡ƒ–‹ ƒŽ †‡• ”‹’–‹‘‘ˆ–Š‡‡š–‡†‡†‘†‡Ž‹•‰‹˜‡‹—’’Ž‡‡–ƒ”›–‡š–ͳǤ ‹‰—”‡ʹ•Š‘™•–Š‡ ‡– •–‡ƒ†›Ǧ•–ƒ–‡   ’”‘†— –‹‘ ˆŽ—š ƒ• ƒ ˆ— –‹‘ ‘ˆ –Š‡ ‘ ‡–”ƒ–‹‘ ‘ˆ –Š‡ •—„•–”ƒ–‡ ›–‘•‘Ž‹  ’ƒŽ‹–‘›ŽǦ‘Ǥ  ‹ ”‡ƒ•‹‰ ›–‘•‘Ž‹  ’ƒŽ‹–‘›ŽǦ‘ ‘ ‡–”ƒ–‹‘ ”‡ˆŽ‡ –• –Š‡ ˆƒ•–‹‰ ‘†‹–‹‘ ™Š‡ –”‹‰Ž› ‡”‹†‡• ˆ”‘ –Š‡ ƒ†‹’‘•‡ •–‘”‡• ƒ”‡ Š›†”‘Ž›œ‡† ƒ† •‡ ”‡–‡† ‹–‘ –Š‡ ‹” —Žƒ–‹‘ǡ –Š—• ’”‘˜‹†‹‰ ‘”‡ •—„•–”ƒ–‡ ˆ‘” –Š‡ Ž‹˜‡”  Ǥ Š‡   ’”‘†— –‹‘ ˆŽ—š •Š‘™‡† ƒ •ƒ–—”ƒ–‹‘ —”˜‡ǡ ‹ ™Š‹ Š –Š‡ ƒš‹— ˆŽ—š ™ƒ• ”‡ƒ Š‡† ƒ– ƒ’’”‘š‹ƒ–‡Ž› ͵ͲɊ ›–‘•‘Ž‹  ’ƒŽ‹–‘›ŽǦ‘ ȋ ‹‰—”‡ ʹȌǤ – Š‹‰Š‡” •—„•–”ƒ–‡ ‘ ‡–”ƒ–‹‘•–Š‡ˆ”‡‡‘ Ž‡˜‡Ž•†‡ Ž‹‡†ǡ‹””‘”‹‰–Š‡‹ ”‡ƒ•‡‘ˆ–Š‡–‘–ƒŽ‘‡•–‡” ‘ ‡–”ƒ–‹‘‹–Š‡ƒ–”‹šȋ ‹‰—”‡ʹȌǤŠ‡–‘–ƒŽ‘ ‘ ‡–”ƒ–‹‘™ƒ•ˆ‹š‡†ƒ–ƒ ‘•–ƒ– ˜ƒŽ—‡ǡƒ•‹’”‡˜‹‘—•‘†‡Ž˜‡”•‹‘•ȏʹʹǡ͵͹Ȑǡ”‡ˆŽ‡ –‹‰–Šƒ–‘„‹‘•›–Š‡•‹•–ƒ‡•’Žƒ ‡ƒ–ƒ •Ž‘™‡”–‹‡• ƒŽ‡Ǥ  Cytosol. DCA. Palmitoyl-CoA (Cчϭϰ-Acyl-CoA) Malonyl-CoA carnitine. DCA FFA. Acyl-carnitine. Acyl-CoA. CoASH. CoASH. carnitine. FFA. CACT. C4-C16. C4-C16. CPT2. C4-C16. Mitochondrion. C4-C16. carnitine. CoQ ETFox. ACOT. FFA. C4-C16. CoASH carnitine. Acyl-carnitine. ETFred. CoASH. Acetyl-CoA CoASH. C4-C16. 2 Acetyl-CoA. ETFQO. ACAT1 C4-ketoacyl-CoA. SCAD. MCAD. VLCAD. ETFox. C4-C6. C4-C16. C6-C16. ETFred. Acetyl-CoA NADH + H+ C4-ketoacyl-CoA NAD+ CoASH. Acetyl-CoA CoASH. HMGCS2 HMG-CoA. HMGCL. Enoyl-CoA. Ketoacyl-CoA. MSCHAD. CoQH2. CoASH. Acyl-CoA. C4-C16. C4-C16. Microsome. ACS. CPT1. MCKAT. ʘ-oxidation. NADH + H+ NAD+. H2O. C4-ketoacyl-CoA. CROT C4-C16. Hydroxyacyl-CoA. MTP. Acetyl-CoA. Acetoacetate. C8-C16. NADH + H+ NAD+. BDH1 ɴ-OH-butyrate. . Figure 1. Schematic representation of the extended human model.‡–ƒ„‘Ž‹–‡•‹„Ž—‡ƒ”‡ ‘•‹†‡”‡† ƒ• „‘—†ƒ”› ‡–ƒ„‘Ž‹–‡• ™‹–Š ˆ‹š‡† ‘ ‡–”ƒ–‹‘•Ǥ Š‡ —†‡”Ž›‹‰ ƒ••—’–‹‘ ‹• –Šƒ– –Š‡‹” ‘ ‡–”ƒ–‹‘• ƒ”‡ †‡–‡”‹‡† Žƒ”‰‡Ž› „› –Š‡ •—””‘—†‹‰ ‡–™‘”Ǥ Š‡ ‘–Š‡” ‡–ƒ„‘Ž‹–‡• ƒ”‡ ˆ”‡‡ ˜ƒ”‹ƒ„Ž‡•ˆ‘”™Š‹ Š‘”†‹ƒ”›†‹ˆˆ‡”‡–‹ƒŽ‡“—ƒ–‹‘•ȋ•ȌŠƒ˜‡„‡‡†‡ˆ‹‡†ȋ•‡‡—’’Ž‡‡–ƒŽ–‡š–ͳ ˆ‘”–Š‡ ‘’Ž‡–‡‘†‡Ž†‡• ”‹’–‹‘ȌǤ›–‘•‘Ž‹ ’ƒŽ‹–‘›ŽǦ‘ȋ‰‹˜‡‹„Ž—‡Ȍ‹•–Š‡•—„•–”ƒ–‡ƒ†‡’–ƒ–ƒ ˆ‹š‡† ‘ ‡–”ƒ–‹‘ǡ™Š‹Ž‡ ›–‘•‘Ž‹ ƒ ›ŽǦ‘‡•–‡”•‘ˆ ƒ”„‘ Šƒ‹Ž‡‰–Š•‘ˆͳͶ‘”Ž‘™‡”ȋ‹†‹ ƒ–‡†„› dͳͶǡ ‹ „Žƒ Ȍ ƒ”‡ ˜ƒ”‹ƒ„Ž‡Ǥ Š‡› ƒ”‡ ‹–‡”‡†‹ƒ–‡ ‡–ƒ„‘Ž‹–‡• †‡”‹˜‡† ˆ”‘ –Š‡ ’ƒ”–‹ƒŽ ‘š‹†ƒ–‹‘ ‘ˆ ’ƒŽ‹–‘›ŽǦ‘ƒ†”‡ › Ž‹‰„›Ǥ. 

(27)  ‘’ƒ”‹•‘ –‘ Chapter 2ǡ ™‡ ‘–‡ –Šƒ– –Š‡ ‘  ‘ ‡–”ƒ–‹‘ †‘‡• ‘– †”‘’ –‘ –Š‡ ’‘‹–™Š‡”‡–Š‡ˆŽ—š•–ƒ”–‡†–‘†‡ Ž‹‡‹–Š‡‡ƒ”Ž‹‡”‘†‡Ž˜‡”•‹‘Ǥ

(28) –‹•’‘••‹„Ž‡–Šƒ––Š‹•‹• ƒ—•‡†„›–Š‡ƒ††‹–‹‘‘ˆ’”‘ ‡••‡•–Šƒ–”‡‰‡‡”ƒ–‡‘ ƒ†”‡†— ‡–Š‡ƒ ——Žƒ–‹‘‘ˆ ‘‡•–‡”•ǤŠ‡†‹ˆˆ‡”‡–’ƒ”ƒ‡–‡”•ˆ‘”–Š‡Š—ƒ‡œ›‡•ƒ›ǡŠ‘™‡˜‡”ǡƒŽ•‘ ‘–”‹„—–‡Ǥ ‡†‹†‘–‹˜‡•–‹‰ƒ–‡–Š‹•ˆ—”–Š‡”Ǥ . ͳ͸͵. 5.

(29) Chapter 5. B. C 3.0. 5000. 12. 10 8 6 4 2 0. free CoA. Intermediate CoA esters. 4000. C4-CoA esters 3000. C6-CoA esters C8-CoA esters. 2000. C10-CoA esters C12-CoA esters. 1000. 50 [Palmitoyl-CoA]CYT ;ʅDͿ. 100. Leak * ɇvExAc-carnCn * ɇvExFFACn * ɇvExDCACn * vacsC16 *. 2.0. 1.0. C14-CoA esters C16-CoA esters. 0. 0. Substrate leak (%). 14. [Metabolite]MAT ;ʅDͿ. Jnadhsink (μmol.min-1.gProtein-1). A. 0. 50. [Palmitoyl-CoA]CYT ;ʅDͿ. 0.0. 0. 100. . 50. [Palmitoyl-CoA]CYT ;ʅDͿ. 100. . Figure 2. The net NADH production flux in the mitochondrionȋ‹Ǥ‡’”‘†— –‹‘„›Ȁ ƒ† ‹—• ‘•—’–‹‘ „› ‡–‘‰‡‡•‹•Ȍ ȋ†‡‘–‡† ‹ –Š‡ ‰”ƒ’Š ƒ• ƒ†Š•‹ǡ •‹ ‡ ƒ– •–‡ƒ†› •–ƒ–‡ –Š‹• ˆŽ—š ‹’Ž‹ ‹–›ƒŽ•‘”‡’”‡•‡–•–Š‡”ƒ–‡‘ˆ  ‘•—’–‹‘„›‘š‹†ƒ–‹˜‡’Š‘•’Š‘”›Žƒ–‹‘ǡ–Š‡•‹ȋAȌǢƒ† –Š‡ ‹–‘ Š‘†”‹ƒŽ ‘ ‡•–‡” ‘ ‡–”ƒ–‹‘•ǡ •—‡† ‘˜‡” ƒ ›ŽǦ‘ǡ ‡‘›ŽǦ‘ǡ Š›†”‘š›Ǧ‡‘›ŽǦ‘ ƒ† ‡–‘ƒ ›ŽǦ‘ǡ •’‡ ‹ˆ‹‡† ’‡” ƒ”„‘Ǧ Šƒ‹ Ž‡‰–Š ȋBȌ ȋ ˆǤ ‹‰—”‡ ͳȌǤ ƒ‡Ž C †‡’‹ –• ǮŽ‡ƒǯ ˆŽ—š‡• ‘ˆ ƒ ›ŽǦ ‰”‘—’•–Šƒ–Ž‡ƒ˜‡–Š‡•›•–‡˜‹ƒ‡š’‘”–‘ˆƒ ›ŽǦ ƒ”‹–‹‡•ƒ† ‘”˜‹ƒ ZǦ‘š‹†ƒ–‹‘ǡƒ†–Š‡ͳ͸Ǧƒ ›ŽǦ ”‡ › Ž‹‰ˆŽ—š˜‹ƒǤŠ‡ˆŽ—š‡•™‡”‡ˆ‹”•– ƒŽ —Žƒ–‡†‹—‹–•‘ˆ –Šƒ–™‘—Ž†Šƒ˜‡„‡‡’”‘†— ‡†‹ˆ –Š‡›Šƒ†„‡‡ˆ—ŽŽ›‘š‹†‹œ‡†ǡ‹Ǥ‡Ǥƒͳ͸Ǧƒ ›ŽˆŽ—š™‘—Ž†„‡—Ž–‹’Ž‹‡†„›͹ǡƒͳͶǦƒ ›ŽˆŽ—š„›͸ǡ‡– ǤŠ‹• ƒŽŽ‘™• †‹”‡ – ‘’ƒ”‹•‘ ‘ˆ –Š‡ ˆŽ—š‡• –‘ –Š‡ ‡–     ˆŽ—š ‹ ’ƒ‡Ž  ƒ† –‘ ‡ƒ Š ‘–Š‡” ȋSupplementary Figure S2ȌǤ—„•‡“—‡–Ž›ǡ–Š‡•‡ˆŽ—š‡•™‡”‡ ‘˜‡”–‡†–‘ƒ’‡” ‡–ƒ‰‡‘ˆ–Š‡’ƒŽ‹–‘›ŽǦ ‘ ‘•—’–‹‘ˆŽ—š‡š’”‡••‡†ƒ• ’”‘†— –‹‘‡“—‹˜ƒŽ‡–•ȋͳͲͲΨȗˆŽ—šȀȋ͹ȗ˜ ’–ͳͳ͸ȌȌǤ.  ‡ƒƒ‰‡ ‘ˆ ƒ ›ŽǦ‘‹‡–‹‡• ‘—– ‘ˆ –Š‡ •›•–‡ ˜‹ƒ ‡š’‘”– ‘” ZǦ‘š‹†ƒ–‹‘ ™ƒ• ˜‡”› •ƒŽŽ ȋ–‘‰‡–Š‡”ƒš‹ƒŽŽ›ʹǤ͹Ψ‘ˆ–Š‡–‘–ƒŽ’ƒŽ‹–‘›ŽǦ‘ ‘•—’–‹‘ˆŽ—šǢȋ ‹‰—”‡ʹǡȌǤŠ‹• ”‡•—Ž–• ‹ ƒ ‡–   ’”‘†— –‹‘ ˆŽ—š •‹‹Žƒ” –‘ –Š‡ ‡š’‡ –‡†   ’”‘†— –‹‘ ˆŽ—š ‹ˆ ƒŽŽ ’ƒŽ‹–‘›ŽǦ‘ ™‘—Ž† „‡ ˆ—ŽŽ› ‘š‹†‹œ‡† ‹ –Š‡  ǡ ‹Ǥ‡Ǥ „ƒ•‡† ‘ ͹š –Š‡ ͳ͸Ǧƒ ›ŽǦ‘ ‘•—’–‹‘ˆŽ—šȋ—’’Ž‡‡–ƒ”›ˆ‹‰—”‡ʹȌǤ ‹ƒŽŽ›ǡ‡–ƒ„‘Ž‹ ‘–”‘ŽƒŽ›•‹•ȋ ˆǤŠƒ’–‡” ʹȌ •Š‘™‡† –Šƒ– ͳ ƒ†   †‡Š›†”‘‰‡ƒ•‡ ȋ Ȍ •Šƒ”‡ ˆŽ—š ‘–”‘Ž ƒ– ʹͷ Ɋ ’ƒŽ‹–‘›ŽǦ‘ǡ „—– ƒ– ƒ– ͳͲͲ Ɋ ’ƒŽ‹–‘›ŽǦ‘ ͳ †‘‡• ‘– ‡š‡”– ƒ› ˆŽ—š ‘–”‘Ž ƒ›‘”‡Ǥ•‡š’‡ –‡†ǡͳŠƒ•ƒ‡‰ƒ–‹˜‡ ‘–”‘Ž‘‘ ǡ™Š‹ Š™ƒ•‘”‡’”‘‘— ‡† ƒ– ͳͲͲ Ɋ ’ƒŽ‹–‘›ŽǦ‘Ǥ Š‹• ‹• „ƒŽƒ ‡† „› ƒ ’‘•‹–‹˜‡ ‘–”‘Ž ‡š‡”–‡† „›   ȋ—’’Ž‡‡–ƒ”›–ƒ„Ž‡ͳȌǤ . Simulating the impact of ACAD deficiencies on the mitochondrial mFAO flux ‡š–ǡ–Š‡‹’ƒ –‘ˆƒ ‘’Ž‡–‡‹ƒ –‹˜ƒ–‹‘‘ˆ‡ƒ Š‘ˆ–Š‡•™ƒ••‹—Žƒ–‡†•‡’ƒ”ƒ–‡Ž›ǡ –‘ ‹‹  –Š‡ ‘””‡•’‘†‹‰ ‡œ›‡ †‡ˆ‹ ‹‡ ‹‡• ‹ ’ƒ–‹‡–• ȏͳͲǡ͵ͺǡ͵ͻȐ ȋ ‹‰—”‡ ͵ȌǤ  ‘’Ž‡–‡ ‹ƒ –‹˜ƒ–‹‘ ‘ˆ –Š‡ ‡œ›‡• ‹• ”‡ƒŽ‹•–‹ ǣ „‘–Š ‹  ȏ͵ͺȐ ƒ†  ȏͶͲȐ ”‡•‹†—ƒŽ ƒ –‹˜‹–‹‡• Ž‘™‡” –Šƒ ͲǤͷΨ Šƒ˜‡ „‡‡ ”‡’‘”–‡† ƒ† ‹  ƒ ”‡•‹†—ƒŽ ƒ –‹˜‹–› Ž‘™‡” –Šƒ ͶΨ Šƒ• „‡‡ ”‡’‘”–‡† ȏͶͳȐǤ Š‡   ‡šŠ‹„‹–‡† –Š‡ Ž‘™‡•–   ’”‘†— –‹‘ ˆŽ—šǡ ˆ‘ŽŽ‘™‡†„› –Š‡  ǡ ™Š‹Ž‡ –Š‡ ˆŽ—š ‹ –Š‡   ‘†‡Ž ™ƒ• ‘Ž› ƒ”‰‹ƒŽŽ›Ž‘™‡”–Šƒ–Šƒ–‘ˆ–Š‡ȋ ‹‰—”‡͵ȌǤŠ‹•”‡ˆŽ‡ –•–Š‡‰‡‡”ƒŽ‘”†‡”‘ˆ†‹•‡ƒ•‡ •‡˜‡”‹–› ‘ˆ –Š‡ Š—ƒ  †‡ˆ‹ ‹‡ ‹‡•ǣ  ‹• —•—ƒŽŽ› ƒ•›’–‘ƒ–‹ ȏ͸Ȑǡ  ’”‡•‡–•‘Ž›†—”‹‰‹–‡” —””‡–‹ŽŽ‡••‘”—’‘ƒ‘–Š‡”–”‹‰‰‡”ȋ•‡‡ƒ„‘˜‡Ȍǡ™Š‹Ž‡ Šƒ•–Š‡‘•–•‡˜‡”‡•›’–‘•ǤŽ‡ƒ”Ž›ǡ–Š‹•‘†‡Ž•‹—Žƒ–‡•–Š‡Š—ƒ†‹•‡ƒ•‡•„‡––‡”–Šƒ –Š‡’”‡˜‹‘—•Ž›’—„Ž‹•Š‡†Š—ƒ‘†‡Žȋ ‹‰—”‡͵ȌǤ‹‡–Š‡ȋ ‹‰—”‡ʹȌƒŽ•‘–Š‡ †‡ˆ‹ ‹‡– ‘†‡Ž• •Š‘™‡† ƒ †‡ Ž‹‡ ‘ˆ ‘  ™‹–Š ‹ ”‡ƒ•‹‰ ’ƒŽ‹–‘›ŽǦ‘ ‘ ‡–”ƒ–‹‘ ȋ ‹‰—”‡͵ǦȌǤ

(30) –Š‡‘†‡Ž–Š‡†‡ Ž‹‡‘ˆ‘ ™ƒ•Ž‡••–Šƒ‹–Š‡Ǥ . ͳ͸Ͷ.

(31) Simulating the impact of modifiers on MCAD deficiency in human liver fatty-acid catabolism. Jnadhsink (μmol.min-1.gProtein-1). A  14 12. WT. 10 8. SCAD KO. 6. MCAD KO. 4. VLCAD KO 2 0. . . [Metabolite]MAT ;ʅDͿ. B. C. 5000. VLCAD KO. D MCAD KO. SCAD KO. free CoA. Intermediate CoA esters. 4000. 5. C4-CoA esters 3000. C6-CoA esters C8-CoA esters. 2000. C10-CoA esters C12-CoA esters. 1000. C14-CoA esters . E. F. 40. VLCAD KO Substrate leak (%). . C16-CoA esters. 0. G 0 MCAD KO. SCAD KO. 30. 0. 20. 0. 10. 0. 0. 0. Leak * ɇvExAc-carnCn * ɇvExFFACn *. ɇvExDCACn * vacsC16 * 0. 50. 100 0. [Palmitoyl-CoA]CYT ;ʅDͿ. 50. [Palmitoyl-CoA]CYT ;ʅDͿ Ǥ. 100 0. 50. [Palmitoyl-CoA]CYT ;ʅDͿ. 100. . Figure 3. The net NADH production flux in the mFAO ȋAȌǡ ‹–‘ Š‘†”‹ƒŽ ‘ ‡•–‡” ‘ ‡–”ƒ–‹‘•ǡ •—‡† ‘˜‡” ƒ ›ŽǦ‘ǡ ‡‘›ŽǦ‘ǡ Š›†”‘š›Ǧ‡‘›ŽǦ‘ ƒ† ‡–‘ƒ ›ŽǦ‘ǡ •’‡ ‹ˆ‹‡† ’‡” ƒ”„‘Ǧ Šƒ‹ Ž‡‰–Š‘ˆȋŠ‡ƒŽ–Š›Ȍƒ†•‹‰Ž‡Ǧ‡œ›‡˜‡”•‹‘•‘ˆ–Š‡‡š–‡†‡†‘†‡ŽȋB-DȌǤƒ‡Ž•E-G†‡’‹ –ǡ ˆ‘”‡ƒ Š•‹‰Ž‡Ǧ‡œ›‡‘†‡Žǡ–Š‡ǮŽ‡ƒǯˆŽ—š‡•‘ˆƒ ›ŽǦ‰”‘—’•–Šƒ–Ž‡ƒ˜‡–Š‡•›•–‡˜‹ƒ‡š’‘”–‘ˆƒ ›ŽǦ ƒ”‹–‹‡• ƒ†  ‘” ˜‹ƒ ZǦ‘š‹†ƒ–‹‘ǡ ƒ† –Š‡ ͳ͸Ǧƒ ›ŽǦ”‡ › Ž‹‰ ˆŽ—š ˜‹ƒ  ƒ• ƒ ’‡” ‡–ƒ‰‡ ‘ˆ –Š‡ ’ƒŽ‹–‘›ŽǦ‘ ‘•—’–‹‘ˆŽ—š‡š’”‡••‡†ƒ• ’”‘†— –‹‘‡“—‹˜ƒŽ‡–•Ǥ.  Š‹• •Š‘—Ž† „‡ ‡š’‡ –‡†ǡ •‹ ‡  ‹• ‘‡ ‘ˆ –Š‡ ˆ‹”•– ‡œ›‡• ‹ –Š‡ ’ƒ–Š™ƒ› ƒ† ƒ †‡ˆ‹ ‹‡ ›’”‡˜‡–•ƒ ——Žƒ–‹‘‘ˆ‘‡•–‡”•†‘™•–”‡ƒǤ ‘”†‹‰Ž›ǡ‹–Š‡ ‘†‡Ž‘Ž›ͳ͸Ǧ‘‡•–‡”•ƒ ——Žƒ–‡†ȋ ‹‰—”‡͵ȌǤ

(32)  ‘–”ƒ•–ǡ‹–Š‡‘†‡Ž–Š‡ †‡ Ž‹‡‘ˆ‘ ™ƒ•Žƒ”‰‡”–Šƒ‹–Š‡‘†‡Žƒ†‹–™ƒ•‡˜‡Žƒ”‰‡”‹–Š‡ ‘†‡ŽǤ

(33) –Š‡•‡ ƒ•‡•ǡ–Š‡†‡ˆ‡ –‹•ˆ—”–Š‡”†‘™•–”‡ƒǡ•— Š–Šƒ–•—„•–”ƒ–‡‡–‡”•‘”ƒŽŽ› ƒ† –Š‡ •–ƒ”–• ƒ ——Žƒ–‹‰Ǥ

(34)  –Š‡   ‘†‡Ž ‘•–Ž› ͺ ƒ† ͳͲ ‘ ‡•–‡”• ƒ ——Žƒ–‡† ȋ ‹‰—”‡ ͵Ȍǡ ™Š‹ Š ‹• ‘•‹•–‡– ™‹–Š –Š‡ ƒ ——Žƒ–‹‘ ‘ˆ ͺ ƒ† ͳͲ ƒ ›ŽǦ ƒ”‹–‹‡•‹„Ž‘‘†•ƒ’Ž‡•ˆ”‘’ƒ–‹‡–•ȏͶʹȂͶ͸ȐǤ

(35) –Š‡‘†‡Žǡƒ ——Žƒ–‹‘‘ˆͶǦ‘‡•–‡”•™ƒ•‘•–’”‘‹‡–ȋ ‹‰—”‡͵Ȍǡ‹ Ž‹‡ ™‹–Š ƒ †‡ˆ‡ – ‹ –Š‡ ‡–ƒ„‘Ž‹• ‘ˆ •Š‘”–Ǧ Šƒ‹ ƒ ›ŽǦ‘ ‡•–‡”• ƒ† ‘„•‡”˜ƒ–‹‘• ‹ ’ƒ–‹‡–•Ǥ Š‡ Ž‡ƒ ˆŽ—š‡•ǡ i.e. –Š‡ •— ‘ˆ –Š‡ ˆŽ—š‡• ‘ˆ ‹ ‘’Ž‡–‡Ž›‘š‹†‹œ‡† ’ƒŽ‹–‘›ŽǦ‘ǡ ™ƒ•˜‡”›•ƒŽŽ‹–Š‡ƒ†‘†‡Ž•ǡƒ•‹–™ƒ•‹–Š‡Š‡ƒŽ–Š›‘†‡Žȋ ˆǤ ‹‰—”‡ ʹǦ ƒ† ‹‰—”‡ ͵ Ǧ ȌǤ

(36)  ‘–”ƒ•–ǡ ‹ –Š‡   ‘†‡Ž –Š‡ Ž‡ƒ ™ƒ• “—‹–‡ ƒ Žƒ”‰‡ ˆ”ƒ –‹‘ ‘ˆ –Š‡ –‘–ƒŽ ’ƒŽ‹–‘›ŽǦ‘ ‘•—’–‹‘ ˆŽ—šǤ Š‡ Žƒ”‰‡” ˆ”ƒ –‹‘ ‘ˆ –Š‡ –‘–ƒŽ Ž‡ƒ ™ƒ•ǡŠ‘™‡˜‡”ǡ”‡ › Ž‡†–Š”‘—‰Šȋ’‹Ž‹‡‹ ‹‰—”‡͵ȌǤŠ‹•”‡ˆŽ‡ –•–Š‡‰‡‡”ƒŽ‘”†‡” ‘ˆ †‹•‡ƒ•‡ •‡˜‡”‹–› ‘ˆ –Š‡ Š—ƒ  †‡ˆ‹ ‹‡ ‹‡•ǣ  ‹• —•—ƒŽŽ› ƒ•›’–‘ƒ–‹ ȏ͸Ȑǡ ’”‡•‡–•‘Ž›†—”‹‰‹–‡” —””‡–‹ŽŽ‡••‘”—’‘ƒ‘–Š‡”–”‹‰‰‡”ȋ•‡‡ƒ„‘˜‡Ȍǡ™Š‹Ž‡ ͳ͸ͷ.

(37) Chapter 5 Šƒ•–Š‡‘•–•‡˜‡”‡•›’–‘•ǤŽ‡ƒ”Ž›ǡ–Š‹•‘†‡Ž•‹—Žƒ–‡•–Š‡Š—ƒ†‹•‡ƒ•‡• „‡––‡” –Šƒ –Š‡ ’”‡˜‹‘—•Ž› ’—„Ž‹•Š‡† Š—ƒ ‘†‡Ž ȋ ‹‰—”‡ ͵ȌǤ ‹‡ –Š‡  ȋ ‹‰—”‡ ʹȌ ƒŽ•‘ –Š‡  †‡ˆ‹ ‹‡– ‘†‡Ž••Š‘™‡† ƒ †‡ Ž‹‡ ‘ˆ ‘  ™‹–Š ‹ ”‡ƒ•‹‰ ’ƒŽ‹–‘›ŽǦ‘ ‘ ‡–”ƒ–‹‘ȋ ‹‰—”‡͵ǦȌǤ

(38) –Š‡‘†‡Ž–Š‡†‡ Ž‹‡‘ˆ‘ ™ƒ•Ž‡••–Šƒ‹ –Š‡ǤŠ‹••Š‘—Ž†„‡‡š’‡ –‡†ǡ•‹ ‡‹•‘‡‘ˆ–Š‡ˆ‹”•–‡œ›‡•‹–Š‡’ƒ–Š™ƒ›ƒ† ƒ †‡ˆ‹ ‹‡ › ’”‡˜‡–• ƒ ——Žƒ–‹‘ ‘ˆ ‘ ‡•–‡”• †‘™•–”‡ƒǤ  ‘”†‹‰Ž›ǡ ‹ –Š‡  ‘†‡Ž‘Ž›ͳ͸Ǧ‘‡•–‡”•ƒ ——Žƒ–‡†ȋ ‹‰—”‡͵ȌǤ

(39)  ‘–”ƒ•–ǡ‹–Š‡‘†‡Ž –Š‡†‡ Ž‹‡‘ˆ‘ ™ƒ•Žƒ”‰‡”–Šƒ‹–Š‡‘†‡Žƒ†‹–™ƒ•‡˜‡Žƒ”‰‡”‹–Š‡ ‘†‡ŽǤ

(40) –Š‡•‡ ƒ•‡•ǡ–Š‡†‡ˆ‡ –‹•ˆ—”–Š‡”†‘™•–”‡ƒǡ•— Š–Šƒ–•—„•–”ƒ–‡‡–‡”•‘”ƒŽŽ› ƒ† –Š‡ •–ƒ”–• ƒ ——Žƒ–‹‰Ǥ

(41)  –Š‡   ‘†‡Ž ‘•–Ž› ͺ ƒ† ͳͲ ‘ ‡•–‡”• ƒ ——Žƒ–‡† ȋ ‹‰—”‡ ͵Ȍǡ ™Š‹ Š ‹• ‘•‹•–‡– ™‹–Š –Š‡ ƒ ——Žƒ–‹‘ ‘ˆ ͺ ƒ† ͳͲ ƒ ›ŽǦ ƒ”‹–‹‡• ‹ „Ž‘‘† •ƒ’Ž‡• ˆ”‘  ’ƒ–‹‡–• ȏͶʹȂͶ͸ȐǤ

(42)  –Š‡   ‘†‡Žǡ ƒ ——Žƒ–‹‘‘ˆͶǦ‘‡•–‡”•™ƒ•‘•–’”‘‹‡–ȋ ‹‰—”‡͵Ȍǡ‹Ž‹‡™‹–Šƒ†‡ˆ‡ –‹–Š‡ ‡–ƒ„‘Ž‹•‘ˆ•Š‘”–Ǧ Šƒ‹ƒ ›ŽǦ‘‡•–‡”•ƒ†‘„•‡”˜ƒ–‹‘•‹’ƒ–‹‡–•ǤŠ‡Ž‡ƒˆŽ—š‡•ǡi.e. –Š‡•—‘ˆ–Š‡ˆŽ—š‡•‘ˆ ‹ ‘’Ž‡–‡Ž›‘š‹†‹œ‡†’ƒŽ‹–‘›ŽǦ‘ǡ™ƒ•˜‡”›•ƒŽŽ‹–Š‡ ƒ†   ‘†‡Ž•ǡ ƒ• ‹– ™ƒ• ‹ –Š‡ Š‡ƒŽ–Š› ‘†‡Ž ȋ ˆǤ ‹‰—”‡ ʹǦ ƒ† ‹‰—”‡ ͵ Ǧ ȌǤ

(43)  ‘–”ƒ•–ǡ‹–Š‡‘†‡Ž–Š‡Ž‡ƒ™ƒ•“—‹–‡ƒŽƒ”‰‡ˆ”ƒ –‹‘‘ˆ–Š‡–‘–ƒŽ’ƒŽ‹–‘›ŽǦ ‘ ‘•—’–‹‘ˆŽ—šǤŠ‡Žƒ”‰‡”ˆ”ƒ –‹‘‘ˆ–Š‡–‘–ƒŽŽ‡ƒ™ƒ•ǡŠ‘™‡˜‡”ǡ”‡ › Ž‡†–Š”‘—‰Š ȋ’‹Ž‹‡‹ ‹‰—”‡͵ȌǤ . Impact of individual variations on the mFAO flux

(44) †‹˜‹†—ƒŽ ˜ƒ”‹ƒ–‹‘• ‹ –Š‡ ‡–ƒ„‘Ž‹  ’ƒ–Š™ƒ›• –Šƒ– •—””‘—† –Š‡   ƒ› ƒˆˆ‡ – –Š‡  ˆŽ—šƒ†–Š‡”‡„›†‹•‡ƒ•‡’”‡•‡–ƒ–‹‘ǤŠ‡”‡ˆ‘”‡ǡƒ—„‡”‘ˆ˜ƒ”‹ƒ–‹‘•™‡”‡–‡•–‡† ‹–Š‡‘†‡Žǡ™‹–Šƒˆ‘ —•‘”‡†— –‹‘‘ˆ–Š‡ƒ˜ƒ‹Žƒ„‹Ž‹–›‘ˆ‘ ‘” ΪǤ‡•‹—Žƒ–‡† –Š‡ ‹’ƒ – ‘ˆ Ž‘™‡” –‘–ƒŽ ‘ ‘ ‡–”ƒ–‹‘ ‹ –Š‡ ƒ–”‹š ȋ”‡ˆŽ‡ –‹‰ ƒ Ž‡•• ƒ –‹˜‡ ‘ „‹‘•›–Š‡•‹• ‘” Ž‘™‡” ‘ ‡–”ƒ–‹‘ ‘ˆ ‹–• ’”‡ —”•‘” ˜‹–ƒ‹ ͷȌǤ ‡ ƒŽ•‘ •‹—Žƒ–‡† –Š‡ ‹’ƒ – ‘ˆ Ž‘™‡” ΪǦ  ”ƒ–‹‘ ȋ”‡ˆŽ‡ –‹‰ ƒ Ž‡•• ƒ –‹˜‡  Ȍǡ –Š‡ ‡ˆˆ‡ – ‘ˆ ƒ Ž‘™‡” ›–‘•‘Ž‹  ƒ† ‹–‘ Š‘†”‹ƒŽ Ǧ ƒ”‹–‹‡ ‘ ‡–”ƒ–‹‘ ȋ”‡ˆŽ‡ –‹‰ ’‘–‡–‹ƒŽŽ› Ž‘™‡” Ǧ ƒ”‹–‹‡Ž‡˜‡Ž•‹’ƒ–‹‡–•Ȍƒ†ƒŽƒ ‘ˆƒ ›ŽǦ ƒ”‹–‹‡‡š’‘”–‹–‘–Š‡„Ž‘‘†ǡƒ•™ƒ• –Š‡ ƒ•‡ ‹ –Š‡ ’—„Ž‹•Š‡† ‹•‘Žƒ–‡†   ‘†‡Ž• ȏʹʹǡͶ͹ȐǤ —”–Š‡”‘”‡ǡ ™‡ •‹—Žƒ–‡† –Š‡ ‡ˆˆ‡ –‘ˆ–Š‡ƒ„•‡ ‡‘ˆͳǡ–Š‡ˆ‹”•–‡œ›‡‘ˆ–Š‡ ‡–‘‰‡‡•‹•’ƒ–Š™ƒ›„›•‡––‹‰‹–ǯ• ƒš–‘œ‡”‘ȋͳαͲȌƒ†–Š‡‹’ƒ –‘ˆ‘ †‘™‘ˆ–Š‡–Š‹‘‡•–‡”ƒ•‡•„›”‡†— ‹‰ ‹–• ƒš –‘ ͳΨ ‘ˆ ‹–• ”‡ˆ‡”‡ ‡ ˜ƒŽ—‡Ǥ ‹ƒŽŽ›ǡ ™‡ •‹—Žƒ–‡† –Š‡ ‡ˆˆ‡ – ‘ˆ ƒ ‘ †‘™ ‘ˆ „›Ž‘™‡”‹‰‹–•ƒš–‘ͳΨ‘ˆ‹–•”‡ˆ‡”‡ ‡ ˜ƒŽ—‡ȋ ‹‰—”‡ͶȌǤ‘•–‘ˆ–Š‡˜ƒ”‹ƒ–‹‘• –Šƒ– ™‡ ‹–”‘†— ‡†ǡ Šƒ† ‘Ž› ƒ ‹‘” ‹’ƒ – ‘ –Š‡ ‡–   ’”‘†— –‹‘ ˆŽ—šǡ ƒ• ƒ „‡ •‡‡ ˆ”‘ –Š‡ ”‡Žƒ–‹˜‡Ž› •ƒŽŽ †‹ˆˆ‡”‡ ‡ „‡–™‡‡ –Š‡ •‘Ž‹† Ž‹‡• ƒ† –Š‡ ‘””‡•’‘†‹‰ †ƒ•Š‡†Ž‹‡•‹ ‹‰—”‡ͶǦ ǤŠ‹•ƒ›”‡ˆŽ‡ ––Šƒ––Š‡Žƒ”‰‡—„‡”‘ˆ‘†‡Ž‡š–‡•‹‘•Šƒ• ƒ†‡–Š‡‘†‡Ž”‡Žƒ–‹˜‡Ž›”‘„—•–ƒ‰ƒ‹•––Š‡•‡˜ƒ”‹ƒ–‹‘•Ǥ ‡†‹†‘––‡•–™Š‡–Š‡”ƒŠ—ƒ‘†‡Ž™‹–Š‘—––Š‡•‡‡š–‡•‹‘•™‘—Ž†„‡‘”‡•‡•‹–‹˜‡ –‘ ”‡†— –‹‘ ‘ˆ –Š‡ ‘‡œ›‡•Ǥ ‡ ‘„•‡”˜‡† ’”‡˜‹‘—•Ž›ǡ Š‘™‡˜‡”ǡ –Šƒ– –Š‡ ”ƒ– ‘†‡Ž ™‹–Š‘—––Š‡‡š–‡•‹‘•ǡ™ƒ•˜‡”›•‡•‹–‹˜‡–‘ Šƒ‰‡•‹–Š‡ ΪȀ ”ƒ–‹‘ȏʹ͸ǡͶͺȐǤŠƒ– ͳŠƒ†Ž‹––Ž‡‡ˆˆ‡ –ȋ ‹‰—”‡ͶȌƒ›„‡†—‡–‘–Š‡ˆƒ ––Šƒ–‹– ƒ–ƒŽ›œ‡•ƒ”‡ƒ –‹‘–Šƒ–‹• ƒŽ•‘ ƒ–ƒŽ›œ‡†„›Ǥ†‡ˆ‹ ‹‡ ›Šƒ†ƒŽƒ”‰‡”‡ˆˆ‡ ––Šƒͳ†‡ˆ‹ ‹‡ ›ȋ ˆǤ ‹‰—”‡Ͷ ƒ† ǡ”‡•’‡ –‹˜‡Ž›ȌǤ  ͳ͸͸.

(45) Simulating the impact of modifiers on MCAD deficiency in human liver fatty-acid catabolism . Jnadhsink (μmol.min-1.gProtein-1). A. B. 14. Jnadhsink (μmol.min-1.gProtein-1). A. D. 10 8 6 4 2 0. 0. 50. [Palmitoyl-CoA]CYT ;ʅDͿ . C. 12. 100 0. . 50. [Palmitoyl-CoA]CYT ;ʅDͿ. B. 14. 100 0. . 50. 100 0. [Palmitoyl-CoA]CYT ;ʅDͿ. . C. 50. [Palmitoyl-CoA]CYT ;ʅDͿ. 100. . 5. 12 WT. 10 8. SCAD KO. 6. MCAD KO. 4 VLCAD KO. 2 0. 0. 50. [Palmitoyl-CoA]CYT ;ʅDͿ. 100 0. 50. 100 0. [Palmitoyl-CoA]CYT ;ʅDͿ. 50. [Palmitoyl-CoA]CYT ;ʅDͿ . 100. . Figure 4. Net NADH production flux ȋ–‡”‡† ƒ†Š•‹Ȍ ‘ˆ  ƒ† •‹‰Ž‡Ǧ‡œ›‡  ˜‡”•‹‘• ‘ˆ –Š‡ ‘†‡Ž •—„Œ‡ –‡† –‘ ƒ††‹–‹‘ƒŽ ‹–‡”˜‡–‹‘•Ǥ Š‡ ‹–‡”˜‡–‹‘• ƒ”‡ Ž‘™‡” –‘–ƒŽ ‘ ‘ ‡–”ƒ–‹‘ ‹ –Š‡ ƒ–”‹šȋʹͷΨ‘ˆ–Š‡”‡ˆ‡”‡ ‡•–ƒ–‡ȌȋAȌǡŽ‘™‡”ΪȀ ”ƒ–‹‘ȋʹͷΨ‘ˆ–Š‡”‡ˆ‡”‡ ‡•–ƒ–‡ȌȋBȌǡŽ‘™‡” ›–‘•‘Ž‹ ƒ†‹–‘ Š‘†”‹ƒŽǦ ƒ”‹–‹‡ ‘ ‡–”ƒ–‹‘ȋʹͷΨ‘ˆ–Š‡”‡ˆ‡”‡ ‡•–ƒ–‡ȌȋCȌǡ‘ƒ ›ŽǦ ƒ”‹–‹‡ ‡š’‘”–‹–‘–Š‡„Ž‘‘†ȋDȌǡ‘ͳȋEȌǡŽ‘™‡” ȋͳΨ‘ˆ–Š‡”‡ˆ‡”‡ ‡•–ƒ–‡ȌȋFȌǡŽ‘™‡”ȋʹͷΨ‘ˆ –Š‡”‡ˆ‡”‡ ‡•–ƒ–‡ȌȋGȌǤƒ•Š‡†Ž‹‡•”‡’”‡•‡––Š‡”‡ˆ‡”‡ ‡•–ƒ–‡‘ˆ–Š‡‘”–Š‡‹†‹ ƒ–‡† ȋ–Š‡•ƒ‡†ƒ–ƒƒ•‹ ‹‰—”‡͵Ȍǡ™Š‹Ž‡•‘Ž‹†Ž‹‡•”‡’”‡•‡––Š‡‹†‹ ƒ–‡†˜ƒ”‹ƒ–‹‘‹–Š‡•‡‘†‡Ž•Ǥ.  ǡŠ‘™‡˜‡”ǡ ‘˜‡”–••—„•–”ƒ–‡•‘ˆƒ”ƒ‰‡‘ˆ ƒ”„‘Ǧ Šƒ‹Ž‡‰–Š•˜ƒ”›‹‰ˆ”‘Ͷ–‹ŽŽ ͳ͸Ǥ  —„•–”ƒ–‡• †‘™ –‘ ͺ ƒ ƒŽ•‘ „‡ ‘˜‡”–‡† „›  ȋ ‹‰—”‡ ͳȌǡ „—–  ‹• ƒ ‡••‡–‹ƒŽ‡œ›‡ˆ‘” ‘˜‡”•‹‘‘ˆ͸Ǧ‡–‘ƒ ›ŽǦ‘ǤˆƒŽŽ˜ƒ”‹ƒ–‹‘•–Šƒ–™‡”‡‹’‘•‡†ǡ–Š‡ ”‡†— –‹‘ ‘ˆ ‡ŽŽ—Žƒ” Ǧ ƒ”‹–‹‡ Ž‡˜‡Ž• Šƒ† –Š‡ •–”‘‰‡•– ‡ˆˆ‡ – ‘   ˆ— –‹‘ ȋ ‹‰—”‡ ͶȌǤ ƒ”‹–‹‡ ‹• ”‡“—‹”‡† ˆ‘” –Š‡ —’–ƒ‡ ‘ˆ ƒ ›ŽǦ‘ ‡•–‡”• –Š”‘—‰Š –Š‡ ͳǦǦʹ •Š—––Ž‡ ȋ ‹‰—”‡ ͳȌ ƒ† ˆ‘” –Š‡ ‡š’‘”– ‘ˆ ƒ ›Ž ‘‹‡–‹‡• ‹ –Š‡ ˆ‘” ‘ˆ ƒ ›ŽǦ ƒ”‹–‹‡•Ǥ

(46) ’ƒ‹”‡– ‘ˆ –Š‡ ‡š’‘”– ‘ˆ ƒ ›ŽǦ ƒ”‹–‹‡• †‹† ‘– ƒˆˆ‡ – –Š‡   ˆŽ—š ȋ ‹‰—”‡ ͶȌǤ Š‡”‡ˆ‘”‡ǡ ƒ† „‡ ƒ—•‡ ͳ Šƒ† •—„•–ƒ–‹ƒŽ ‘–”‘Ž ‘˜‡” –Š‡ ˆŽ—šǡ ™‡ ‘ Ž—†‡ –Šƒ– –Š‡ ”‡†— –‹‘‘ˆ ‡ŽŽ—Žƒ” ƒ”‹–‹‡Ž‡˜‡Ž•ƒˆˆ‡ –•–Š‡ ˆŽ—š–Š”‘—‰Š‹–•”‘Ž‡‹–Š‡•Š—––Ž‡Ǥ . Impact of acyl-CoA recycling on the mFAO flux Š‡–Š‹‘‡•–‡”ƒ•‡•ȋ•ȌŠƒ˜‡„‡‡”‡’‘”–‡†–‘ ‘–”‹„—–‡–‘–Š‡ ˆŽ—šȏʹ͹Ȃ͵ͲȐǤŠ‡ •–Šƒ–ƒ”‡’”‘†— ‡†‹–Š‹•”‡ƒ –‹‘ ƒ„‡‡š’‘”–‡†‘””‡ƒ –‹˜ƒ–‡†„›ǤŠ‡”‡ˆ‘”‡ǡ‹– ™ƒ•‹˜‡•–‹‰ƒ–‡†™Š‡–Š‡”–Š‡ ”‡ƒ –‹˜ƒ–‹‘ƒ†ƒ ›ŽǦ‘”‡ › Ž‹‰Šƒ•ƒ‹’ƒ –‘–Š‡  ˆŽ—šǤ ‘”–Š‹•ǡ™‡Ž‘™‡”‡†–Š‡ƒš‘ˆ–‘ͳΨ‘ˆ‹–•”‡ˆ‡”‡ ‡˜ƒŽ—‡Ǥ

(47) ˆ™‡‘Ž›Ž‘™‡” –Š‡  ƒ’ƒ ‹–›ǡ  ƒ •–‹ŽŽ „‡ ’”‘†— ‡† „›  ƒ† ‡š’‘”–‡†ǡ „—– ‘– ”‡ƒ –‹˜ƒ–‡†Ǥ ‘™‡”‹‰Š‘™‡˜‡”ǡ†‹†‘–ƒˆˆ‡ ––Š‡ˆŽ—š‡••—„•–ƒ–‹ƒŽŽ›‹–Š‡‘”ƒ›‘ˆ–Š‡ • ȋ ‹‰—”‡ ͷȌǤ

(48)  ƒ††‹–‹‘ǡ ‡–ƒ„‘Ž‹  ‘–”‘Ž ƒŽ›•‹• •Š‘™‡† –Šƒ–  ‡š‡”–‡† ‘ ˆŽ—š ‘–”‘Ž ‹ –Š‡ ”‡ˆ‡”‡ ‡ ‘†‡Ž ƒ† –Š‹• ™ƒ• ‘– Šƒ‰‡† ™Š‡ ‹– ™ƒ• ‹’ƒ‹”‡† ȋ ˆǤ —’’Ž‡‡–ƒ”›–ƒ„Ž‡•ͳƒ†ʹȌǤŠ‡‘ †‘™‘ˆ‡Šƒ ‡†–Š‡ƒ ——Žƒ–‹‘‘ˆ ‘ ‡•–‡”•ƒ†–Š‡ ‘””‡•’‘†‹‰ ”‡†— –‹‘ ‘ˆ ˆ”‡‡ ‘  ‹ –Š‡   ƒ†   ‘†‡Ž•ȋ ‹‰—”‡ͷǦȌǤ ͳ͸͹.

(49) Chapter 5.   . Jnadhsink (μmol.min-1.gProtein-1). A. [Metabolite]MAT ;ʅDͿ. B. 14 12. WT. 10 8. SCAD KO. 6. MCAD KO. 4. VLCAD KO 2 0. 0. 50. 100. WT.  VLCAD KO. C. 5000. MCAD KO D. SCAD KO E. 4000. free CoA 3000 2000. Intermediate CoA esters. 1000 0. 0. 50. [Palmitoyl-CoA]CYT ;ʅDͿ. 100 0. 50. [Palmitoyl-CoA]CYT ;ʅDͿ. 100 0. 50. [Palmitoyl-CoA]CYT ;ʅDͿ. 100 0. 50. [Palmitoyl-CoA]CYT ;ʅDͿ. 100. . ‹‰—”‡ ͷǤ ‹—Žƒ–‹‘ ”‡•—Ž–• ‘ˆ –Š‡ Ǧ‘ †‘™ –‘ ͳΨ ‘ˆ ‹–• ”‡ˆ‡”‡ ‡ ˜ƒŽ—‡Ǥ ‡’‘”–‡† ƒ”‡ –Š‡ ‡–   ’”‘†— –‹‘ ˆŽ—š ‹ –Š‡   ȋȌǡ ‹–‘ Š‘†”‹ƒŽ ˆ”‡‡ ‘ ƒ† ‘ ‡•–‡” ‘ ‡–”ƒ–‹‘• ȋǦȌ

(50)  ’ƒ‡Ž–Š‡†ƒ•Š‡†Ž‹‡•”‡’”‡•‡––Š‡”‡ˆ‡”‡ ‡•–ƒ–‡‘ˆ–Š‡‘”–Š‡‹†‹ ƒ–‡†ȋ–Š‡•ƒ‡†ƒ–ƒ ƒ•‹ ‹‰—”‡͵Ȍǡ™Š‹Ž‡•‘Ž‹†Ž‹‡•”‡’”‡•‡––Š‡‘ †‘™Ǥ.  ’’ƒ”‡–Ž›–Š‡–Š‹‘‡•–‡”ƒ•‡Ȃ › Ž‡”‡Ž‹‡˜‡†–Š‡•‡“—‡•–”ƒ–‹‘‘ˆ‘ ǤŠ‡ˆŽ—š‡•‘ˆ –Š‡Ž‡ƒƒ‰‡”‡ƒ –‹‘”ƒ–‡•”‡ƒ‹‡†Ž‘™‹–Š‹•‘†‡Žȋ—’’Ž‡‡–ƒ”› ‹‰—”‡͵ȌǤ‘–Š‡” ™ƒ›–‘‹˜‡•–‹‰ƒ–‡™Š‡–Š‡”–Š‡ ”‡ƒ –‹˜ƒ–‹‘ƒ†ƒ ›ŽǦ‘”‡ › Ž‹‰Šƒ•ƒ‹’ƒ –‘–Š‡  ˆŽ—š‹•„›‹’ƒ‹”‹‰–Š‡ ‘˜‡”•‹‘‘ˆ–Š‡”‡ƒ –‹˜ƒ–‡† •ȋ ›–‘•‘Ž‹ ͳͶǦͶƒ ›ŽǦ‘ ‡•–‡”•Ȍ–‘ƒ ›ŽǦ ƒ”‹–‹‡•„›ͳǤŠ‹•™ƒ•†‘‡„›ƒ‹‰ͳ‘”‡ͳ͸Ǧ•’‡ ‹ˆ‹ ǡi.e. „› Ž‘™‡”‹‰ –Š‡ ƒš ˜ƒŽ—‡• ‘ˆ ͳ ˆ‘” –Š‡ ͳͶǦͶ ”‡ƒ –‹‘• ƒ† „› Ž‘™‡”‹‰ ‹–• ƒˆˆ‹‹–› –‘™ƒ”†•ͳͶǦͶƒ ›ŽǦ‘‡•–‡”•ȋ•‡‡—’’Ž‡‡–ƒ”›–‡š–ͳˆ‘”–Š‡ ‘””‡•’‘†‹‰‹‡–‹  ’ƒ”ƒ‡–‡”•ȌǤ Š‡ Žƒ––‡” ™ƒ• ƒ Š‹‡˜‡† „› ‹ ”‡ƒ•‹‰ –Š‡ ‘””‡•’‘†‹‰  ˜ƒŽ—‡•Ǥ Š‹• ‘†‹ˆ‹ ƒ–‹‘Šƒ†Ž‹––Ž‡‡ˆˆ‡ –‘–Š‡ ˆŽ—š‹–Š‡ǡƒ†ȋ ‹‰—”‡ ͸ȌǤŠ‡ ˆŽ—š‘ˆ–Š‡™ƒ••—„•–ƒ–‹ƒŽŽ›”‡†— ‡†Š‘™‡˜‡”„›–Š‡‹’ƒ‹”‡– ‘ˆƒ ›ŽǦ‘”‡ › Ž‹‰–Š”‘—‰Šͳȋ ‹‰—”‡͸ȌǤ

(51)  ‘–”ƒ•––‘–Š‡”‡ˆ‡”‡ ‡‘†‡Žǡ–Š‡ͳ͸Ǧ •’‡ ‹ˆ‹  ͳ ƒ‹–ƒ‹‡† ͳͲͲΨ ‘–”‘Ž ‘˜‡” –Š‡   ˆŽ—š ‘˜‡” –Š‡ ™Š‘Ž‡ ”ƒ‰‡ ‘ˆ ›–‘•‘Ž‹  ’ƒŽ‹–‘›ŽǦ‘ ‘ ‡–”ƒ–‹‘• ȋ—’’Ž‡‡–ƒ”› ƒ„Ž‡ ͵ȌǤ —”’”‹•‹‰Ž›ǡ –Š‡ ƒ ——Žƒ–‹‘ ‘ˆ ‹–‘ Š‘†”‹ƒŽ ‘ ‡•–‡”•™ƒ• ‘’Ž‡–‡Ž›ƒ„‘Ž‹•Š‡† ‹–Š‡  ƒ†  ‘†‡Ž ™‹–Š ƒ ͳ͸Ǧ•’‡ ‹ˆ‹  ͳ ȋ ‹‰—”‡ ͸ǦȌǤ ‘–ƒ„Ž›ǡ –Š‡ ›–‘•‘Ž‹  ‘ ‡•–‡” ‘ ‡–”ƒ–‹‘• ‘ˆ ƒŽŽ –Š‡ ‘†‡Ž• ƒ ——Žƒ–‡† –‘ ˜‡”› Š‹‰Š Ž‡˜‡Ž•ǡ •‹ ‡ ‘ ‘‹‡–› ‘•‡”˜ƒ–‹‘ ˆ‘” ›–‘•‘Ž‹  ‘ ™ƒ• ‹’‘•‡† ȋ—’’Ž‡‡–ƒ”› –ƒ„Ž‡ ͶȌǤ Š‡ ˆŽ—š‡• ‘ˆ –Š‡ Ž‡ƒƒ‰‡ ”‡ƒ –‹‘ ”ƒ–‡• ”‡ƒ‹‡† Ž‘™ ‹ –Š‹• ‘†‡Ž ȋ—’’Ž‡‡–ƒ”› ‹‰—”‡ ͶȌǤ Š‡   ‘†‡Ž ™‹–Š ƒ ͳ͸Ǧ•’‡ ‹ˆ‹  ͳ ™ƒ• — Š ‘”‡ •‡•‹–‹˜‡ –‘ ƒ††‹–‹‘ƒŽ –”‹‰‰‡”•ǣ ™Š‡ ‡‹–Š‡”–Š‡–‘–ƒŽ‹–‘ Š‘†”‹ƒŽ‘‘”–Š‡–‘–ƒŽǦ ƒ”‹–‹‡Ž‡˜‡Ž™ƒ•”‡†— ‡†„›ͳͲΨǡ–Š‹•Ž‡† –‘ ƒ •–”‘‰ ”‡†— –‹‘ ‘ˆ –Š‡   ˆŽ—šǡ †‘™ –‘ –Š‡ Ž‡˜‡Ž ‘ˆ –Š‡   ‘†‡Ž ȋ ‹‰—”‡ ͸ ǡ ȌǤ ‘•‹†‡”‹‰ –Š‡ •‡˜‡”‡Ž› ‘ˆ ǡ ‹• ‹– Ž‹‡Ž› –Šƒ– –Š‹• ‹• ƒ ˆŽ—š ”‡†— –‹‘ –Šƒ– ‘””‡•’‘†•–‘ƒ Ž‹‹ ƒŽ’Š‡‘–›’‡Ǥ  . ͳ͸ͺ.

(52) Simulating the impact of modifiers on MCAD deficiency in human liver fatty-acid catabolism. . Jnadhsink (μmol.min-1.gProtein-1). A 14 12 WT. 10 8. SCAD KO. 6. MCAD KO. 4 VLCAD KO. 2 0. 0. 50. B 5000. [Metabolite]MAT ;ʅDͿ. . . 100. WT. . VLCAD KO C. MCAD KO D. SCAD KO E. 5. 4000 free CoA 3000 2000 Intermediate CoA esters. 1000 0. 0. 50. 100 0. 50. 100 0. [Palmitoyl-CoA]CYT ;ʅDͿ. [Palmitoyl-CoA]CYT ;ʅDͿ. 50. [Palmitoyl-CoA]CYT ;ʅDͿ. . F Jnadhsink (μmol.min-1.gProtein-1). . . 100 0. . 50. [Palmitoyl-CoA]CYT ;ʅDͿ. 100. . G 14 12. WT. 10 8. SCAD KO. 6. MCAD KO. 4. VLCAD KO 2 0. 0. 50. [Palmitoyl-CoA]CYT ;ʅDͿ. 100 0. . 50. [Palmitoyl-CoA]CYT ;ʅDͿ. 100. . Figure 6. Simulation results of the extended model with a CPT1 with reduced activity and affinity towards C14-C4 acyl-CoA substrates. Š‡’ƒ”ƒ‡–‡”˜ƒŽ—‡•–Šƒ–™‡”‡ Šƒ‰‡†–‘‘„–ƒ‹–Š‹•ͳǡƒ”‡ ‰‹˜‡‹–Š‡•‡ ‘†–ƒ„Ž‡‹•—’’Ž‡‡–ƒ”›–‡š–ͳǤ‡’‘”–‡†ƒ”‡–Š‡–‘–ƒŽ ’”‘†— –‹‘ˆŽ—š‹–Š‡   ȋAȌ ƒ† –Š‡ ‹–‘ Š‘†”‹ƒŽ ‘  ƒ† ‘ ‡•–‡” ‘ ‡–”ƒ–‹‘• ȋͳ͸ǦͶ ƒ ›ŽǦ‘ ‡•–‡”•Ȍ ȋB-EȌǤ ƒ‡Ž• F-G †‹•’Žƒ› –Š‡ ‡–   ’”‘†— –‹‘ ˆŽ—š ȋ–‡”‡† ƒ†Š•‹Ȍ ‘ˆ  ƒ† •‹‰Ž‡Ǧ‡œ›‡  ˜‡”•‹‘• ‘ˆ –Š‡ ‘†‡Ž •—„Œ‡ –‡† –‘ ƒ††‹–‹‘ƒŽ ‹–‡”˜‡–‹‘•Ǥ Š‡ ‹–‡”˜‡–‹‘• ƒ”‡ Ž‘™‡” –‘–ƒŽ ‘ ‘ ‡–”ƒ–‹‘ ‹ –Š‡ ƒ–”‹š ȋͻͲΨ ‘ˆ –Š‡ ”‡ˆ‡”‡ ‡ •–ƒ–‡Ȍ ȋFȌ ƒ† Ž‘™‡” ›–‘•‘Ž‹  ƒ† ‹–‘ Š‘†”‹ƒŽ Ǧ ƒ”‹–‹‡ ‘ ‡–”ƒ–‹‘ȋͻͲΨ‘ˆ–Š‡”‡ˆ‡”‡ ‡•–ƒ–‡ȌȋGȌǤƒ•Š‡†Ž‹‡•”‡’”‡•‡––Š‡”‡ˆ‡”‡ ‡•–ƒ–‡‘ˆ–Š‡  ‘” –Š‡ ‹†‹ ƒ–‡†   ȋ–Š‡ •ƒ‡ †ƒ–ƒ ƒ• ‹ Figure 3Ȍǡ ™Š‹Ž‡ •‘Ž‹† Ž‹‡• ”‡’”‡•‡– –Š‡ ‹†‹ ƒ–‡† ˜ƒ”‹ƒ–‹‘‹–Š‡•‡‘†‡Ž•Ǥ. . Discussion Š‡   ’ƒ–Š™ƒ› ‹• ‹–”‹ ƒ–‡Ž› ‘‡ –‡† –‘ •‡˜‡”ƒŽ ’ƒ–Š™ƒ›• ‘ˆ ‡‡”‰› ‡–ƒ„‘Ž‹•Ǥ Š‡•‡ ’ƒ–Š™ƒ›• ƒ› ’Žƒ› ƒ ’ƒ”–‹ —Žƒ”Ž› ”— ‹ƒŽ ”‘Ž‡ ‹ –Š‡ ˆ— –‹‘ ‘ˆ   ‹ –Š‡ Ž‹˜‡” †—”‹‰ˆƒ•–‹‰‘” ‘†‹–‹‘•‘ˆŠ‹‰Š‡‡”‰›†‡ƒ†Ǥ

(53) –Š‹••–—†›ǡ™‡‰‡‡”ƒ–‡†ˆ‘”–Š‡ˆ‹”•– –‹‡ǡ ƒ †›ƒ‹  ‘’—–ƒ–‹‘ƒŽ ‘†‡Ž ‘ˆ   ‹ Š—ƒ Ž‹˜‡” ™‹–Š ‡š–‡•‹‘• ‹–‘ –Š‡ ƒŒ‘” ’ƒ–Š™ƒ›• –Šƒ– ƒˆˆ‡ – –Š‡ ƒ ›ŽǦ‘ ƒ† ‘  ‘ ‡–”ƒ–‹‘•Ǥ — Š ƒ ‘†‡Ž ‹• ƒ ‹’‘”–ƒ––‘‘Ž–‘‰‡–ƒ‘”‡”‡ƒŽ‹•–‹ ‹’”‡••‹‘‘ˆ–Š‡‡ Šƒ‹••Ž‡ƒ†‹‰–‘”‘„—•–‡•• ƒ† ˜—Ž‡”ƒ„‹Ž‹–› ‹  Ǥ ƒ”–‹ —Žƒ”Ž›ǡ ‹ ǡ †‹•‡ƒ•‡ •‡˜‡”‹–› ƒ‘– „‡ ’”‡†‹ –‡† ‡˜‡ ™‹–Š‹ –Š‡ •ƒ‡ —–ƒ–‹‘ ȏ͹ȂͳͷȐǤ —” ƒ‹ ™ƒ• –‘ ‹˜‡•–‹‰ƒ–‡ ™Š‡–Š‡” –Š‡ †‹ˆˆ‡”‡– †‹•‡ƒ•‡ ’”‡•‡–ƒ–‹‘• ‘ˆ ’ƒ–‹‡–• ‘—Ž† –Š‡‘”‡–‹ ƒŽŽ› „‡ ƒ—•‡† „› ‹†‹˜‹†—ƒŽ ˜ƒ”‹ƒ–‹‘• ‹ –Š‡ •—””‘—†‹‰ ‡–™‘”Ǥ  ‘’—–ƒ–‹‘ƒŽ ‘†‡Ž †‘‡• ‘– ’”‘˜‡ –Šƒ– •— Š ˜ƒ”‹ƒ–‹‘•. ͳ͸ͻ.

(54) Chapter 5 ƒ –—ƒŽŽ› ’Žƒ› ƒ ”‘Ž‡ ‹ ’ƒ–‹‡–•ǡ „—– –Š‡› ‰‹˜‡ ‹•‹‰Š– ‹ ™Š‹ Š ˜ƒ”‹ƒ–‹‘•ǡ ‹ˆ –Š‡› ‘ —””‡†ǡ ‘—Ž†Šƒ˜‡–Š‡•–”‘‰‡•–‹’ƒ –in vivoǤ ‘”–Š‹•™‡ Šƒ”ƒ –‡”‹œ‡†–Š‡‘†‡Žƒ†‹–”‘†— ‡† ’‡”–—”„ƒ–‹‘•–Šƒ–™‡”‡‡š’‡ –‡†–‘„‡”‡Ž‡˜ƒ–‹Ǥ ‡–ƒ„‘Ž‹  ‘–”‘ŽƒƒŽ›•‹••Š‘™‡†–Šƒ–ͳ•Šƒ”‡† ‘–”‘Ž™‹–Š †‡Š›†”‘‰‡ƒ•‡‹–Š‡ ‘†‡ŽǤ ͳ Ž‘•– ˆŽ—š ‘–”‘Ž ƒ– Š‹‰Š ’ƒŽ‹–‘›ŽǦ‘ ‘ ‡–”ƒ–‹‘•Ǥ Š‹• ‹• †‹ˆˆ‡”‡– ˆ”‘ –Š‡’”‡˜‹‘—•Ž›’—„Ž‹•Š‡†”ƒ–‘†‡Žȋ™‹–Š‘—–‡š–‡•‹‘•Ȍ‹™Š‹ Šͳ‰‘–ƒ‡‰ƒ–‹˜‡ˆŽ—š ‘–”‘Ž ‘‡ˆˆ‹ ‹‡–ƒ–Š‹‰Š•—„•–”ƒ–‡ ‘ ‡–”ƒ–‹‘•ȏͶͺȐǤŠ‡”‡Žƒ–‹˜‡ˆŽ—š‡•‘ˆ–Š‡ ‘†‡Ž• ™‡”‡ ‹ ƒ‰”‡‡‡– ™‹–Š ‰‡‡”ƒŽ †‹•‡ƒ•‡ •‡˜‡”‹–› ‘ˆ  ‹ Š—ƒ• ȋ”‡ˆ‡”‡ ‡  ƒ†  ‘†‡Ž•ȌǤ

(55)  ƒ††‹–‹‘ǡ –Š‡   ‘†‡Ž• •Š‘™‡† ƒ ›ŽǦ‘ ’”‘ˆ‹Ž‡• ‹ –Š‡ ‹–‘ Š‘†”‹ƒŽ ƒ–”‹š –Šƒ– ƒ”‡ •‹‹Žƒ” –‘ –Š‡ ‘””‡•’‘†‹‰ ƒ ›ŽǦ ƒ”‹–‹‡ ’”‘ˆ‹Ž‡• ‹ ’ƒ–‹‡–•Ǥƒ•‡†‘‡š’‡ –‡†‹’‘”–ƒ ‡‘ˆ•‡˜‡”ƒŽ‡œ›‡•ƒ†‡–ƒ„‘Ž‹–‡•‹ǡ™‡ †‡–‡”‹‡†–Š‡‡ˆˆ‡ –‘ˆ Šƒ‰‹‰•‡Ž‡ –”‡Žƒ–‡†’ƒ”ƒ‡–‡”•‘–Š‡ˆŽ—š‘ˆ–Š‡ƒ†  ‘†‡Ž•Ǥ ‘•– ‘ˆ –Š‡•‡ ’ƒ”ƒ‡–‡”• Šƒ† ƒ •ƒŽŽ ‡ˆˆ‡ – ‘ –Š‡ ˆŽ—š‡• ‹ –Š‡   ‘†‡Ž•Ǥ ‘™‡”‹‰ Ǧ ƒ”‹–‹‡ǡ Š‘™‡˜‡”ǡ Šƒ† ƒ ‹†‹• ”‹‹ƒ–‡Ž› •–”‘‰ ‡ˆˆ‡ – ‘ ƒŽŽ –Š‡ ‘†‡Ž•Ǥ ‡‡š–‹˜‡•–‹‰ƒ–‡†–Š‡‹’‘”–ƒ ‡‘ˆ ”‡ › Ž‹‰‹–Š‹•‘†‡Žǡ–Š”‘—‰Š–Š‡ˆ—–‹Ž‡ › Ž‡ ‘ˆ ‹–‘ Š‘†”‹ƒŽ ƒ ›ŽǦ‘ Š›†”‘Ž›•‹•ǡ ‡š’‘”– ‹–‘ –Š‡ ›–‘•‘Žǡ ”‡ƒ –‹˜ƒ–‹‘ „›  ƒ† —’–ƒ‡„ƒ ‹–‘–Š‡‹–‘ Š‘†”‹ƒǤ ‘™‡˜‡”ǡ‹’ƒ‹”‡†ƒ –‹˜‹–›†‹†‘–ƒˆˆ‡ ––Š‡  ˆŽ—š‹ƒ›‘ˆ–Š‡‘†‡Ž•Ǥ‘–‡–‹ƒŽŽ›ǡ–Š‡‹’ƒ –‘ˆ–Š‹• › Ž‡™ƒ•‹‹ƒŽ†—‡–‘ –Š‡”‡Žƒ–‹˜‡Ž›•ƒŽŽˆŽ—š–Š”‘—‰ŠǤ Ž—šƒƒŽ›•‹•‡š’‡”‹‡–•in vitro ‘—Ž†’”‘˜‹†‡‘”‡ ‹ˆ‘”ƒ–‹‘‘–Š‡”ƒ–‹‘‘ˆ˜‡”•—• ˆŽ—š‹ ‡ŽŽ•ǡ‹‘”†‡”–‘„‡ƒ„Ž‡–‘•‹—Žƒ–‡–Š‡ ”‘Ž‡‘ˆ–Š‡Ǧ‡†‹ƒ–‡†”‡ƒ –‹˜ƒ–‹‘•›•–‡‘”‡”‡ƒŽ‹•–‹ ƒŽŽ›Ǥ ‹ƒŽŽ›ǡ™‡‹˜‡•–‹‰ƒ–‡†–Š‡‡ˆˆ‡ –‘ˆ Šƒ‰‹‰ͳ‹‡–‹ •ǡ–‘•–—†›‹–•”‘Ž‡‹–Š‡”‡ › Ž‹‰ ‘ˆ ˜‹ƒǤ

(56) –‡”‡•–‹‰Ž›ǡ’ƒ”–‹ —Žƒ”Ž›–Š‡˜‡”•‹‘‘ˆ–Š‡‘†‡Ž™ƒ••‡•‹–‹˜‡ –‘ƒŽ–‡”ƒ–‹‘•‘ˆ–Š‡’ƒ”ƒ‡–‡”•‹˜‘Ž˜‡†‹”‡ › Ž‹‰‘ˆͶǦͳͶƒ ›ŽǦ‘‡•–‡”•Ǥ

(57) ƒ††‹–‹‘ǡ in silico ’‡”–—”„ƒ–‹‘•–Šƒ–Šƒ†‘’Š‡‘–›’‡‹–Š‡”‡ˆ‡”‡ ‡‘†‡Žǡ”‡•—Ž–‡†‹ƒ •–”‘‰†‡ ”‡ƒ•‡‘ˆ–Š‡ ˆŽ—š‹–Š‡‘†‡Ž™‹–Š–Š‡ƒŽ–‡”‡†ͳ‹‡–‹ •Ǥ‡ —””‡–Ž›Šƒ˜‡‘‡˜‹†‡ ‡ˆ‘”–Š‡‡š‹•–‡ ‡‘ˆ—–ƒ–‹‘•‹ͳ–Šƒ–Šƒ˜‡•— Š‡ˆˆ‡ –•‘ ͳ ‹‡–‹ •Ǥ ‹˜‡ –Šƒ– ͳ ‹• ‘™ –‘ Šƒ˜‡ ƒ Š‹‰Š ‘–”‘Ž ‘˜‡”   ˆŽ—š —†‡” •’‡ ‹ˆ‹  ‘†‹–‹‘• ȏͶͻǡͷͲȐ ƒ† –Šƒ– ‘—” ‘†‡Ž ’”‡†‹ –• •— Š ƒ •–”‘‰ ‡ˆˆ‡ – ‘ˆ ƒ ͳ ‹‡–‹ • ‹ –Š‡   ‘†‡Žǡ ‹– ƒ› „‡ ‹–‡”‡•–‹‰ –‘ ‹˜‡•–‹‰ƒ–‡ ™Š‡–Š‡” ͳ ‹‰Š– ’Žƒ›ƒ”‘Ž‡‹–Š‡˜—Ž‡”ƒ„‹Ž‹–›‘ˆ•‘‡•›’–‘ƒ–‹ ‹†‹˜‹†—ƒŽ•Ǥ‘‹˜‡•–‹‰ƒ–‡–Š‹•ǡ ‹–™‘—Ž†„‡”‡Ž‡˜ƒ––‘‹˜‡•–‹‰ƒ–‡—–ƒ–‹‘•‹–Š‡ͳ‰‡‡‹–Š‡‰‡‡”ƒŽ’‘’—Žƒ–‹‘ƒ† ‹ •›’–‘ƒ–‹  ˜‡”•—• ƒ•›’–‘ƒ–‹   †‡ˆ‹ ‹‡– Š‹Ž†”‡Ǥ ‘”‡‘˜‡”ǡ ‡š‘‡ •‡“—‡ ‹‰‘ˆ•›’–‘ƒ–‹ ˜‡”•—•ƒ•›’–‘ƒ–‹  Š‹Ž†”‡ƒ››‹‡Ž† ƒ†‹†ƒ–‡‰‡‡• –Šƒ– ƒ„‡–‡•–‡†ˆ— –‹‘ƒŽŽ›‹–Š‡ ‘’—–ƒ–‹‘ƒŽ‘†‡ŽǤŠ‹••Š‘—Ž†ƒŽŽ‘™—•–‘•‡Ž‡ ––Š‡ ‘•–’”‘‹•‹‰ ƒ†‹†ƒ–‡•ˆ‘”ˆ—”–Š‡”‹˜‹–”‘–‡•–‹‰Ǥ

(58) –Š‹•‹‹–‹ƒŽ•–—†›™‡ Šƒ˜‡‘–›‡– ‘•‹†‡”‡† ‡”–ƒ‹ˆƒ –‘”•ǡ”‡ƒ –‹‘•‘”’ƒ–Š™ƒ›•Ǥ ‘” ‹•–ƒ ‡ǡ™‡†‹†‘–ƒŽŽ‘™ˆ‘” ‘•‡”˜‡†‘‹‡–‹‡•‘ˆ ƒ”‹–‹‡‹–Š‡ƒ–”‹šƒ† ›–‘•‘Žƒ† –‘–ƒŽ‘ȋˆ”‡‡ƒ†ƒ ›Žƒ–‡†‘Ȍ‹–Š‡ ›–‘•‘Žǡƒ•–Š‡•‡ ‘—Ž†Ž‹‹––Š‡ƒ ›ŽǦ ƒ”‹–‹‡ƒ† ‘ ‡•–‡” ‘ ‡–”ƒ–‹‘• ‹ –Š‡ ‘†‡ŽǤ ‡ †‘ ‘– –Š‹ –Šƒ– –Š‹• ™‹ŽŽ ‹˜ƒŽ‹†ƒ–‡ –Š‡ ‘ Ž—•‹‘• ‘ˆ –Š‹• •–—†›Ǥ ‡ Šƒ˜‡ ƒŽ•‘ ‘– ”‡’‘”–‡† ™Š‹ Š ’ƒ”ƒ‡–‡”• ƒ› Šƒ˜‡ ‘–”‹„—–‡† –‘ ƒ ƒ„•‡ ‡ ‹ ˆŽ—š †‡ Ž‹‡ ƒ• ™ƒ• ‘„•‡”˜‡† ‹ –Š‡  ”ƒ– ‘†‡Ž ‘ˆ –Š‡ ‹•‘Žƒ–‡† ǡ„—–‘–‹‹–Š‡˜‡”•‹‘‘ˆ–Š‡ˆ‹––‡†‘—•‡‘†‡Ž‘ˆ–Š‡‹•‘Žƒ–‡† Ǥ ‡‘–‡–Šƒ–‹ȏʹʹȐǡ™Š‡”‡ƒ‘—•‡ƒ†Š—ƒ‘†‡Ž‘ˆ‹•‘Žƒ–‡ ™ƒ•’”‡•‡–‡†–Š‹• ͳ͹Ͳ.

(59) Simulating the impact of modifiers on MCAD deficiency in human liver fatty-acid catabolism †‹ˆˆ‡”‡ ‡™ƒ•ƒŽ•‘‘–‹˜‡•–‹‰ƒ–‡†ǡ’‘–‡–‹ƒŽŽ›–‘ˆ‘ —•‘ƒ–Š‡”‘Ž‡‘ˆ‡œ›‡’”‘‹• —‹–› ‘ –Š‡ ˆŽ—š ƒ† ‡–ƒ„‘Ž‹–‡ ’”‘ˆ‹Ž‡•Ǥ ‡”‡ ™‡ ˆ‘ —•‡† ‘ –Š‡ ‡ˆˆ‡ – ‘ˆ ‰‡‡–‹  ƒ† ‡˜‹”‘‡–ƒŽ‘†‹ˆ‹‡”•‘ ˆŽ—š‹ƒ†‘–‡–Šƒ–‹–™ƒ•‘–‡ ‡••ƒ”›ˆ‘”–Š‡ ‘†‡Ž• –‘ •Š‘™ ˆŽ—š †‡ Ž‹‡ ‹ ‘”†‡” –‘ ƒ•™‡” ‘—” ”‡•‡ƒ” Š “—‡•–‹‘Ǥ ‡ Šƒ˜‡ –Š‡”‡ˆ‘”‡ †‡‡‡† ‹– ‘– ‡ ‡••ƒ”› –‘ ”‡’‘”– ™Š‹ Š ’ƒ”ƒ‡–‡”• ‘” ‘„‹ƒ–‹‘ ‘ˆ ’ƒ”ƒ‡–‡”• ƒˆˆ‡ – –Š‡ ’”‡•‡ ‡ ‘” ƒ„•‡ ‡ ‘ˆ ˆŽ—š †‡ Ž‹‡ ‹ –Š‹• •–—†›Ǥ ‡ ƒŽ•‘ ƒ‡ –Š‡ ’”‡Ž‹‹ƒ”› ‘ Ž—•‹‘ –Šƒ– ˆŽ—š †‡ Ž‹‡ ‹• ‘– ƒ ‡ ‡••ƒ”› ‘” ’‡”•‹•–‡– ’Š‡‘‡‘ ‡˜‡ ‹ ‹•‘Žƒ–‡†   ‘†‡Ž•Ǥ ‡ Šƒ˜‡ ƒŽ•‘ ‘– ‹ Ž—†‡† ‹–‘ Š‘†”‹ƒŽ ‡†‹—Ǧ Šƒ‹  ”‡ƒ –‹˜ƒ–‹‘ǡ ›–‘•‘Ž‹  ƒ ›ŽǦ‘ Š›†”‘Ž›•‹• ƒ† ’‡”‘š‹•‘ƒŽ ˆƒ––›Ǧƒ ‹† „‡–ƒ ‘š‹†ƒ–‹‘ ‘ˆ ‡†‹—Ǧ Šƒ‹ •Ǥ ‘™‡˜‡”ǡ ‹ –Š‹• ‹‹–‹ƒŽ •–—†› ™‡ Šƒ˜‡ †‡ ‹†‡† –‘ ˆ‘ —• ‘ –Š‡ Šƒ”ƒ –‡”‹œƒ–‹‘ ‘ˆ ƒ Š—ƒ‘†‡Ž ‘–ƒ‹‹‰–Š‡‘•–‹’‘”–ƒ–”‡ƒ –‹‘•ƒ†’ƒ–Š™ƒ›•ˆ‘”™Š‹ Š•—„•–ƒ–‹ƒŽ ‡˜‹†‡ ‡Šƒ•„‡‡‰‹˜‡ˆ‘”–Š‡‹””‘Ž‡‹ ˆŽ—šǤŠ‹•’”‡Ž‹‹ƒ”›‘†‡Ž‹•–Š‡”‡ˆ‘”‡ƒŽ•‘ •ƒŽŽ‡”ƒ†‡ƒ•‹‡”–‘ Šƒ”ƒ –‡”‹œ‡Ǥ•‹†‹ ƒ–‡†ǡ–Š‡ƒ„•‡ ‡‘ˆ‡Ž‡‡–•‹–Š‡‘†‡Ž†‘‡• ‘– ‡ ‡••ƒ”‹Ž› ‹˜ƒŽ‹†ƒ–‡ –Š‡ ‘ Ž—•‹‘• ‹ –Š‹• •–—†›ǡ „—– ‹•–‡ƒ† ‘ˆˆ‡” ‡™ ƒ˜‡—‡• ˆ‘” ‹†‡–‹ˆ›‹‰‘†‹ˆ‹‡”•–Šƒ– ‘—Ž†ƒˆˆ‡ –•›’–‘ƒ–‘Ž‘‰›‹‹•’‡ ‹ˆ‹ ƒ† ‹ ‰‡‡”ƒŽǤ . Materials and Methods Model construction and simulation Š‡ ‘†‡Ž ™ƒ• „—‹Ž– ƒ† –Š‡ •‹—Žƒ–‹‘• ƒ† ƒŽ —Žƒ–‹‘• ™‡”‡ †‘‡ ‹ ‘Žˆ”ƒ ƒ–Š‡ƒ–‹ ƒ ȋ‘Žˆ”ƒ ‡•‡ƒ” Šǡ

(60)  Ǥǡ Šƒ’ƒ‹‰ǡ

(61) ǡ Ȍǡ ˜‡”•‹‘ ͳͳǤ͵ǤͲǤͲǤ  ˆ—ŽŽ †‡• ”‹’–‹‘ ‘ˆ –Š‡ ‘†‡Ž ‡“—ƒ–‹‘• ‹• ‰‹˜‡ ‹ —’’Ž‡‡–ƒ”› ‡š– ͳǤ ŽŽ –Š‡ •–‡ƒ†›Ǧ•–ƒ–‡ †ƒ–ƒ ™‡”‡ ‰‡‡”ƒ–‡† ˆ”‘ –Š‡ •–‡ƒ†›Ǧ•–ƒ–‡ ‹‹–‹ƒŽ ‘†‹–‹‘ ƒ– ƒ ›–‘•‘Ž‹  ’ƒŽ‹–‘›ŽǦ‘ ‘ ‡–”ƒ–‹‘ ȋȏ’ƒŽ‹–‘›ŽǦ‘ȐȌ ‘ˆ ͲǤͳ Ɋǡ ™Š‹ Š ‹• ‡šƒ –Ž› ƒ• †‘‡ ‹ ‘—” ’”‡˜‹‘—• ’ƒ’‡” ȏʹͳȐǤ Š‡ ƒ–Š‡ƒ–‹ ƒ ˆ— –‹‘• ‘Ž˜‡ ƒ† ‹†‘‘–™‡”‡—•‡† –‘‰‡‡”ƒ–‡–Š‡•‹—Žƒ–‹‘”‡•—Ž–•ǡƒ•†‘‡‹ȏ͵͹ǡͷͳȐǤŠ‡‘†‡ŽŠƒ•—Ž–‹’Ž‡ ‹†‡’‡†‡–ˆŽ—š‡•Ǥ ‡”‡ǡ™‡ˆ‘ —•‡†‘–Š‡‡–‹–‘ Š‘†”‹ƒŽ ’”‘†— –‹‘ˆŽ—šǡ™Š‹ Š‡“—ƒŽ• –Š‡‹’Ž‹‡†‡š–‡”ƒŽ ”‡‘š‹†ƒ–‹‘”ƒ–‡–Šƒ–™‘—Ž†”‡•—Ž–‹–Š‡ƒ‹–‡ƒ ‡‘ˆƒ ‘•–ƒ– ΪǦ  ”ƒ–‹‘ǤŠ‡”‡ˆ‘”‡ǡ™‡—•‡†–Š‡–‡”ƒ†Š•‹–‘†‡’‹ ––Š‡‡– ’”‘†— –‹‘ˆŽ—š‡•‹›Ǧ ƒš‡•‘ˆ–Š‡‰”ƒ’Š•‹–Š‹••–—†›ȋ ƒ†Š•‹Ȍǡƒ• ™ƒ•†‘‡‹‘—”’”‡˜‹‘—•’ƒ’‡”•ȏʹ͸ǡͷͳȐǤ‡†‹†‘– Š‡ ‹ˆ–Š‡•–‡ƒ†›•–ƒ–‡™ƒ•—‹“—‡Ǥ . Flux control analysis Ž—š ‘–”‘Ž ‘‡ˆˆ‹ ‹‡–•™‡”‡ƒ’’”‘š‹ƒ–‡†ƒ ‘”†‹‰–‘ǣ. . . ௃. ௗ௟௡௃Ȁௗ௣. ‫ܥ‬௘௡௭௬௠௘ ൌ డ௟௡௩Ȁడ௣ ൎ ο௏. ο௃. ೘ೌೣǡ೐೙೥೤೘೐. ή. ௏೘ೌೣǡ೐೙೥೤೘೐ ௃.  . . . ȋͳȌ. ™Š‡”‡p†‡‘–‡•ƒ’ƒ”ƒ‡–‡”–Šƒ–‘Ž›ƒˆˆ‡ –•–Š‡”ƒ–‡‘ˆ–Š‡‡œ›‡–Šƒ–‹•ƒƒŽ›œ‡†ǤVmax™ƒ•—•‡† •‹ ‡–Š‡”ƒ–‡•‘ˆƒŽŽ”‡ƒ –‹‘•™‡”‡’”‘’‘”–‹‘ƒŽ–‘–Š‹•’ƒ”ƒ‡–‡”Ǥ ‘”–Š‡ˆ‹‹–‡ Šƒ‰‡†‡‘–‡†„› 'ƒ’‡” ‡–ƒ‰‡„‡Ž‘™͵Ψ–ƒ‡ǡƒ†–Š‡”‡•—Ž–™ƒ•ƒ ‡’–‡†‹ˆ–Š‡•—‘ˆƒŽŽˆŽ—š ‘–”‘Ž ‘‡ˆˆ‹ ‹‡–• ‹–Š‡‘†‡Ž™ƒ•‡“—ƒŽ–‘ͳȏͷʹǡͷ͵ȐǤ  References ͳǤ ‘—–‡ǡƒ†‡”• Ǥ‰‡‡”ƒŽ‹–”‘†— –‹‘–‘–Š‡„‹‘ Š‡‹•–”›‘ˆ‹–‘ Š‘†”‹ƒŽ ˆƒ––› ƒ ‹†ȾǦ‘š‹†ƒ–‹‘Ǥ 

(62) Š‡”‹–‡–ƒ„‹•ǤʹͲͳͲǢ͵͵ȋͷȌǣͶ͸ͻȂ͹͹Ǥ ʹǤ ƒ–‘ ǡ ƒ”–Ž‡–– ǡ ‘—”ˆƒ”œƒ Ǥ ƒƒŽ‹ƒ ‹–‘ Š‘†”‹ƒŽ „‡–ƒǦ‘š‹†ƒ–‹‘Ǥ ‹‘ Š‡ Ǥ ͳͻͻ͸Ǣ͵ʹͲǣ͵ͶͷȂͷ͹Ǥ ͵Ǥ ‘—–‡ ǡ ‹‘Žƒ–‡ ǡ ‡–—”ƒ  Ǥǡ ƒ†‡”•  Ǥ Š‡ ‹‘ Š‡‹•–”› ƒ† Š›•‹‘Ž‘‰› ‘ˆ. ͳ͹ͳ. 5.

(63) Chapter 5. ͶǤ. ͷǤ ͸Ǥ. ͹Ǥ. ͺǤ. ͻǤ. ͳͲǤ. ͳͳǤ. ͳʹǤ. ͳ͵Ǥ. ͳͶǤ. ͳͷǤ ͳ͸Ǥ ͳ͹Ǥ ͳͺǤ ͳͻǤ ʹͲǤ ʹͳǤ. ͳ͹ʹ. ‹–‘ Š‘†”‹ƒŽ ƒ––›  ‹† ȾǦš‹†ƒ–‹‘ ƒ†

(64) –• ‡‡–‹  ‹•‘”†‡”•Ǥ — ‡˜ Š›•‹‘ŽǤ ʹͲͳ͸Ǣ͹ͺȋͳȌǣʹ͵ȂͶͶǤ ˜ƒ—‡ǡ‘Ž‡”Ǧ‘—™ǡ ‡”†‹‰ǡŽ‡‡‡”ǡ‘Ž–‡”• ǡ˜ƒ‹Œ– ǡƒ”–‹‡• ǡ ‹‡œ‡Ǧ‘‹‰ǡ ‡‹‡”ǡ‡”‡–‹‡” ǡ ”‘‡ǡ‡‹Œ‰‘—† ǡ‡”• ǡƒ‡”Ǥ ‹˜‹‰‘–Š‡‡†‰‡ǣ—„•–”ƒ–‡ ‘’‡–‹–‹‘‡š’Žƒ‹•Ž‘••‘ˆ”‘„—•–‡••‹‹–‘ Š‘†”‹ƒŽˆƒ––›Ǧ ƒ ‹†‘š‹†ƒ–‹‘†‹•‘”†‡”•Ǥ‹‘ŽǤʹͲͳ͸ǢͳͶȋͳȌǣͳȂͳͷǤ ‹ƒŽ†‘ ǡ ƒ–‡” ǡ ‡‡––  Ǥ ƒ––›  ‹† ‘š‹†ƒ–‹‘ ‹•‘”†‡”•Ǥ — ‡˜ Š›•‹‘ŽǤ ʹͲͲʹǢ͸ͶȋͳȌǣͶ͹͹ȂͷͲʹǤ ‘—–‡ ǡ ‹‘Žƒ–‡ ǡ ‡–—”ƒ  ǡ ƒ†‡”•  Ǥ Š‡ ‹‘ Š‡‹•–”› ƒ† Š›•‹‘Ž‘‰› ‘ˆ ‹–‘ Š‘†”‹ƒŽ ƒ––›  ‹† ȾǦš‹†ƒ–‹‘ ƒ†

(65) –• ‡‡–‹  ‹•‘”†‡”•Ǥ — ‡˜ Š›•‹‘ŽǤ ʹͲͳͷǢ͹ͺǣʹ͵ȂͶͶǤ ‡”• ǡ‡‹Œ‰‘—† ǡƒ–‡”Šƒ ǡ ‡”˜‡” ǡ˜ƒ†‡‡”‰ǡƒ—‡” ǡ‹– Ǥ Š‡ƒ–—”ƒŽŠ‹•–‘”›‘ˆ‡†‹—Ǧ Šƒ‹ƒ ›Ž‘†‡Š›†”‘‰‡ƒ•‡†‡ˆ‹ ‹‡ ›‹–Š‡‡–Š‡”Žƒ†•ǣ Ž‹‹ ƒŽ’”‡•‡–ƒ–‹‘ƒ†‘—– ‘‡Ǥ ‡†‹ƒ–”ǤʹͲͲ͸ǢͳͶͺȋͷȌǤ ‡”• ǡ‘‡”ǡ••‡ǡ‘•ǡ—‹–‡” ǡƒ–‡”Šƒ ǡ‹‡œ‡Ǧ‘‹‰ǡƒ†‡”• ǡ ‘†‡‡Ž ǡ‘‡„‡” ǡ‡ƒ–‡ǡ‹– ǡ‡‹Œ‰‘—† Ǥ‡‘ƒ–ƒŽ• ”‡‡‹‰ˆ‘”‡†‹—Ǧ Šƒ‹ ƒ ›ŽǦ‘ †‡Š›†”‘‰‡ƒ•‡ ȋȌ †‡ˆ‹ ‹‡ › ‹ Š‡ ‡–Š‡”Žƒ†•ǣ Š‡ ‹’‘”–ƒ ‡ ‘ˆ ‡œ›‡ƒƒŽ›•‹•–‘ƒ• ‡”–ƒ‹–”—‡†‡ˆ‹ ‹‡ ›Ǥ 

(66) Š‡”‹–‡–ƒ„‹•ǤʹͲͲͺǢ͵ͳȋͳȌǣͺͺȂͻ͸Ǥ ‘—™ǡ‹– ǡ‹‡œ‡Ǧ‘‹‰ǡ‘•‰”ƒƒˆǦ†‡‘‡”ǡ ‡”†‹‰ǡ‡‹Œ‰‘—†Ǧ ǡ‡”•  Ǥ

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University of Groningen Exploring the mechanisms underlying the phenotype of MCAD deficiency with Systems Medicine Martines, Anne-Claire

JCPT1C16 [CoASH]MAT JNAD production [palmitoyl-CoA]CYT ʹͷɊ ͳͲͲɊ ʹͷɊ ͳͲͲɊ ʹͷɊ ͳͲͲɊ Vcpt1 0.59 0.00 0.61 0.06 -0.24 -1.11 Vfcact ͲǤͲͳ ͲǤͲͲ ͲǤͲͳ ͲǤͲͲ ͲǤͲͲ ͲǤͲͲ