Publication

The promiscuous enzyme medium-chain 3-keto-acyl-CoA thiolase triggers a vicious cycle in fatty-acid beta-oxidation

Martines, A-C. M. F., van Eunen, K., Reijngoud, D-J. & Bakker, B. M., 3-Apr-2017, In : PLoS Computational Biology. 13, 4, 22 p., e1005461.

Research output: Contribution to journalArticleAcademicpeer-review

APA

Martines, A-C. M. F., van Eunen, K., Reijngoud, D-J., & Bakker, B. M. (2017). The promiscuous enzyme medium-chain 3-keto-acyl-CoA thiolase triggers a vicious cycle in fatty-acid beta-oxidation. PLoS Computational Biology, 13(4), [e1005461]. https://doi.org/10.1371/journal.pcbi.1005461

Author

Martines, Anne-Claire M. F. ; van Eunen, Karen ; Reijngoud, Dirk-Jan ; Bakker, Barbara M. / The promiscuous enzyme medium-chain 3-keto-acyl-CoA thiolase triggers a vicious cycle in fatty-acid beta-oxidation. In: PLoS Computational Biology. 2017 ; Vol. 13, No. 4.

Harvard

Martines, A-CMF, van Eunen, K, Reijngoud, D-J & Bakker, BM 2017, 'The promiscuous enzyme medium-chain 3-keto-acyl-CoA thiolase triggers a vicious cycle in fatty-acid beta-oxidation', PLoS Computational Biology, vol. 13, no. 4, e1005461. https://doi.org/10.1371/journal.pcbi.1005461

Standard

The promiscuous enzyme medium-chain 3-keto-acyl-CoA thiolase triggers a vicious cycle in fatty-acid beta-oxidation. / Martines, Anne-Claire M. F.; van Eunen, Karen; Reijngoud, Dirk-Jan; Bakker, Barbara M.

In: PLoS Computational Biology, Vol. 13, No. 4, e1005461, 03.04.2017.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Martines A-CMF, van Eunen K, Reijngoud D-J, Bakker BM. The promiscuous enzyme medium-chain 3-keto-acyl-CoA thiolase triggers a vicious cycle in fatty-acid beta-oxidation. PLoS Computational Biology. 2017 Apr 3;13(4). e1005461. https://doi.org/10.1371/journal.pcbi.1005461


BibTeX

@article{9457eb20a2ba4856a3875cf2e570144a,
title = "The promiscuous enzyme medium-chain 3-keto-acyl-CoA thiolase triggers a vicious cycle in fatty-acid beta-oxidation",
abstract = "Mitochondrial fatty-acid beta-oxidation (mFAO) plays a central role in mammalian energy metabolism. Multiple severe diseases are associated with defects in this pathway. Its kinetic structure is characterized by a complex wiring of which the functional implications have hardly been explored. Repetitive cycles of reversible reactions, each cycle shortening the fatty acid by two carbon atoms, evoke competition between intermediates of different chain lengths for a common set of 'promiscuous' enzymes (enzymes with activity towards multiple substrates). In our validated kinetic model of the pathway, substrate overload causes a steep and detrimental flux decline. Here, we unravel the underlying mechanism and the role of enzyme promiscuity in it. Comparison of alternative model versions elucidated the role of promiscuity of individual enzymes. Promiscuity of the last enzyme of the pathway, medium-chain ketoacyl-CoA thiolase (MCKAT), was both necessary and sufficient to elicit the flux decline. Subsequently, Metabolic Control Analysis revealed that MCKAT had insufficient capacity to cope with high substrate influx. Next, we quantified the internal metabolic regulation, revealing a vicious cycle around MCKAT. Upon substrate overload, MCKAT's ketoacyl-CoA substrates started to accumulate. The unfavourable equilibrium constant of the preceding enzyme, medium/short-chain hydroxyacyl-CoA dehydrogenase, worked as an amplifier, leading to accumulation of upstream CoA esters, including acyl-CoA esters. These acyl-CoA esters are at the same time products of MCKAT and inhibited its already low activity further. Finally, the accumulation of CoA esters led to a sequestration of free CoA. CoA being a cofactor for MCKAT, its sequestration limited the MCKAT activity even further, thus completing the vicious cycle. Since CoA is also a substrate for distant enzymes, it efficiently communicated the 'traffic jam' at MCKAT to the entire pathway. This novel mechanism provides a basis to explore the role of mFAO in disease and elucidate similar principles in other pathways of lipid metabolism.",
keywords = "COA DEHYDROGENASE-DEFICIENCY, RAT-LIVER MITOCHONDRIA, METABOLIC-CONTROL ANALYSIS, COENZYME-A DEHYDROGENASE, COMPLEX-I, HYPOGLYCEMIA, DISORDERS, PURIFICATION, BIOCHEMISTRY, MECHANISM",
author = "Martines, {Anne-Claire M. F.} and {van Eunen}, Karen and Dirk-Jan Reijngoud and Bakker, {Barbara M.}",
year = "2017",
month = "4",
day = "3",
doi = "10.1371/journal.pcbi.1005461",
language = "English",
volume = "13",
journal = "PLoS Computational Biology",
issn = "1553-7358",
publisher = "PUBLIC LIBRARY SCIENCE",
number = "4",

}

RIS

TY - JOUR

T1 - The promiscuous enzyme medium-chain 3-keto-acyl-CoA thiolase triggers a vicious cycle in fatty-acid beta-oxidation

AU - Martines, Anne-Claire M. F.

AU - van Eunen, Karen

AU - Reijngoud, Dirk-Jan

AU - Bakker, Barbara M.

PY - 2017/4/3

Y1 - 2017/4/3

N2 - Mitochondrial fatty-acid beta-oxidation (mFAO) plays a central role in mammalian energy metabolism. Multiple severe diseases are associated with defects in this pathway. Its kinetic structure is characterized by a complex wiring of which the functional implications have hardly been explored. Repetitive cycles of reversible reactions, each cycle shortening the fatty acid by two carbon atoms, evoke competition between intermediates of different chain lengths for a common set of 'promiscuous' enzymes (enzymes with activity towards multiple substrates). In our validated kinetic model of the pathway, substrate overload causes a steep and detrimental flux decline. Here, we unravel the underlying mechanism and the role of enzyme promiscuity in it. Comparison of alternative model versions elucidated the role of promiscuity of individual enzymes. Promiscuity of the last enzyme of the pathway, medium-chain ketoacyl-CoA thiolase (MCKAT), was both necessary and sufficient to elicit the flux decline. Subsequently, Metabolic Control Analysis revealed that MCKAT had insufficient capacity to cope with high substrate influx. Next, we quantified the internal metabolic regulation, revealing a vicious cycle around MCKAT. Upon substrate overload, MCKAT's ketoacyl-CoA substrates started to accumulate. The unfavourable equilibrium constant of the preceding enzyme, medium/short-chain hydroxyacyl-CoA dehydrogenase, worked as an amplifier, leading to accumulation of upstream CoA esters, including acyl-CoA esters. These acyl-CoA esters are at the same time products of MCKAT and inhibited its already low activity further. Finally, the accumulation of CoA esters led to a sequestration of free CoA. CoA being a cofactor for MCKAT, its sequestration limited the MCKAT activity even further, thus completing the vicious cycle. Since CoA is also a substrate for distant enzymes, it efficiently communicated the 'traffic jam' at MCKAT to the entire pathway. This novel mechanism provides a basis to explore the role of mFAO in disease and elucidate similar principles in other pathways of lipid metabolism.

AB - Mitochondrial fatty-acid beta-oxidation (mFAO) plays a central role in mammalian energy metabolism. Multiple severe diseases are associated with defects in this pathway. Its kinetic structure is characterized by a complex wiring of which the functional implications have hardly been explored. Repetitive cycles of reversible reactions, each cycle shortening the fatty acid by two carbon atoms, evoke competition between intermediates of different chain lengths for a common set of 'promiscuous' enzymes (enzymes with activity towards multiple substrates). In our validated kinetic model of the pathway, substrate overload causes a steep and detrimental flux decline. Here, we unravel the underlying mechanism and the role of enzyme promiscuity in it. Comparison of alternative model versions elucidated the role of promiscuity of individual enzymes. Promiscuity of the last enzyme of the pathway, medium-chain ketoacyl-CoA thiolase (MCKAT), was both necessary and sufficient to elicit the flux decline. Subsequently, Metabolic Control Analysis revealed that MCKAT had insufficient capacity to cope with high substrate influx. Next, we quantified the internal metabolic regulation, revealing a vicious cycle around MCKAT. Upon substrate overload, MCKAT's ketoacyl-CoA substrates started to accumulate. The unfavourable equilibrium constant of the preceding enzyme, medium/short-chain hydroxyacyl-CoA dehydrogenase, worked as an amplifier, leading to accumulation of upstream CoA esters, including acyl-CoA esters. These acyl-CoA esters are at the same time products of MCKAT and inhibited its already low activity further. Finally, the accumulation of CoA esters led to a sequestration of free CoA. CoA being a cofactor for MCKAT, its sequestration limited the MCKAT activity even further, thus completing the vicious cycle. Since CoA is also a substrate for distant enzymes, it efficiently communicated the 'traffic jam' at MCKAT to the entire pathway. This novel mechanism provides a basis to explore the role of mFAO in disease and elucidate similar principles in other pathways of lipid metabolism.

KW - COA DEHYDROGENASE-DEFICIENCY

KW - RAT-LIVER MITOCHONDRIA

KW - METABOLIC-CONTROL ANALYSIS

KW - COENZYME-A DEHYDROGENASE

KW - COMPLEX-I

KW - HYPOGLYCEMIA

KW - DISORDERS

KW - PURIFICATION

KW - BIOCHEMISTRY

KW - MECHANISM

U2 - 10.1371/journal.pcbi.1005461

DO - 10.1371/journal.pcbi.1005461

M3 - Article

VL - 13

JO - PLoS Computational Biology

JF - PLoS Computational Biology

SN - 1553-7358

IS - 4

M1 - e1005461

ER -

ID: 46962939