H55N polymorphism as a likely cause of variation in citrate synthase activity of mouse skeletal muscle

Aivaras Ratkevicius, Andrew M Carroll, Audrius Kilikevicius, Tomas Venckunas, Kevin T McDermott, Stuart R Gray, Henning Wackerhage, Arimantas Lionikas

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Citrate synthase (CS) is an enzyme of the Krebs cycle that plays a key role in mitochondrial metabolism. The aim of this study was to investigate the mechanisms underlying low activity of citrate synthase (CS) in A/J mice compared with other inbred strains of mice. Enzyme activity, protein content, and mRNA levels of CS were studied in the quadriceps muscles of A/J, BALB/cByJ, C57BL/6J, C3H/HeJ, DBA/2J, and PWD/PhJ strains of mice. Cytochrome c protein content was also measured. The results of the study indicate that A/J mice have a 50-65% reduction in CS activity compared with other strains despite similar levels of Cs mRNA and lack of differences in CS and cytochrome c protein content. CS from A/J mice also showed lower Michaelis constant (K(m)) for both acetyl CoA and oxaloacetate compared with the other strains of mice. In silico analysis of the genomic sequence identified a nonsynonymous single nucleotide polymorphism (SNP) (rs29358506, H55N) in Cs gene occurring near the site of the protein interacting with acetyl CoA. Allelic variants of the polymorphism segregated with the catalytic properties of CS enzyme among the strains. In summary, H55N polymorphism in Cs could be the underlying cause of low CS activity and its high affinity for substrates in A/J mice compared with other strains. This SNP might also play a role in resistance to obesity of A/J mice.
Original languageEnglish
Pages (from-to)96-102
Number of pages7
JournalPhysiological Genomics
Volume42A
Issue number2
DOIs
Publication statusPublished - 1 Oct 2010

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Citrate (si)-Synthase
Skeletal Muscle
Acetyl Coenzyme A
Cytochromes c
Single Nucleotide Polymorphism
Proteins
Enzymes
Oxaloacetic Acid
Messenger RNA
Inbred Strains Mice
Citric Acid Cycle
Quadriceps Muscle
Computer Simulation
Sequence Analysis
Obesity

Keywords

  • amino acid sequence
  • animals
  • citrate (si)-synthase
  • cytochromes c
  • gene expression regulation, enzymologic
  • mice
  • molecular sequence data
  • polymorphism, single nucleotide
  • quadriceps muscle
  • RNA, messenger
  • sequence alignment
  • substrate specificity

Cite this

H55N polymorphism as a likely cause of variation in citrate synthase activity of mouse skeletal muscle. / Ratkevicius, Aivaras; Carroll, Andrew M; Kilikevicius, Audrius; Venckunas, Tomas; McDermott, Kevin T; Gray, Stuart R; Wackerhage, Henning; Lionikas, Arimantas.

In: Physiological Genomics, Vol. 42A, No. 2, 01.10.2010, p. 96-102.

Research output: Contribution to journalArticle

Ratkevicius, A, Carroll, AM, Kilikevicius, A, Venckunas, T, McDermott, KT, Gray, SR, Wackerhage, H & Lionikas, A 2010, 'H55N polymorphism as a likely cause of variation in citrate synthase activity of mouse skeletal muscle', Physiological Genomics, vol. 42A, no. 2, pp. 96-102. https://doi.org/10.1152/physiolgenomics.00066.2010
Ratkevicius, Aivaras ; Carroll, Andrew M ; Kilikevicius, Audrius ; Venckunas, Tomas ; McDermott, Kevin T ; Gray, Stuart R ; Wackerhage, Henning ; Lionikas, Arimantas. / H55N polymorphism as a likely cause of variation in citrate synthase activity of mouse skeletal muscle. In: Physiological Genomics. 2010 ; Vol. 42A, No. 2. pp. 96-102.
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AU - Wackerhage, Henning

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N2 - Citrate synthase (CS) is an enzyme of the Krebs cycle that plays a key role in mitochondrial metabolism. The aim of this study was to investigate the mechanisms underlying low activity of citrate synthase (CS) in A/J mice compared with other inbred strains of mice. Enzyme activity, protein content, and mRNA levels of CS were studied in the quadriceps muscles of A/J, BALB/cByJ, C57BL/6J, C3H/HeJ, DBA/2J, and PWD/PhJ strains of mice. Cytochrome c protein content was also measured. The results of the study indicate that A/J mice have a 50-65% reduction in CS activity compared with other strains despite similar levels of Cs mRNA and lack of differences in CS and cytochrome c protein content. CS from A/J mice also showed lower Michaelis constant (K(m)) for both acetyl CoA and oxaloacetate compared with the other strains of mice. In silico analysis of the genomic sequence identified a nonsynonymous single nucleotide polymorphism (SNP) (rs29358506, H55N) in Cs gene occurring near the site of the protein interacting with acetyl CoA. Allelic variants of the polymorphism segregated with the catalytic properties of CS enzyme among the strains. In summary, H55N polymorphism in Cs could be the underlying cause of low CS activity and its high affinity for substrates in A/J mice compared with other strains. This SNP might also play a role in resistance to obesity of A/J mice.

AB - Citrate synthase (CS) is an enzyme of the Krebs cycle that plays a key role in mitochondrial metabolism. The aim of this study was to investigate the mechanisms underlying low activity of citrate synthase (CS) in A/J mice compared with other inbred strains of mice. Enzyme activity, protein content, and mRNA levels of CS were studied in the quadriceps muscles of A/J, BALB/cByJ, C57BL/6J, C3H/HeJ, DBA/2J, and PWD/PhJ strains of mice. Cytochrome c protein content was also measured. The results of the study indicate that A/J mice have a 50-65% reduction in CS activity compared with other strains despite similar levels of Cs mRNA and lack of differences in CS and cytochrome c protein content. CS from A/J mice also showed lower Michaelis constant (K(m)) for both acetyl CoA and oxaloacetate compared with the other strains of mice. In silico analysis of the genomic sequence identified a nonsynonymous single nucleotide polymorphism (SNP) (rs29358506, H55N) in Cs gene occurring near the site of the protein interacting with acetyl CoA. Allelic variants of the polymorphism segregated with the catalytic properties of CS enzyme among the strains. In summary, H55N polymorphism in Cs could be the underlying cause of low CS activity and its high affinity for substrates in A/J mice compared with other strains. This SNP might also play a role in resistance to obesity of A/J mice.

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