The common K333Q polymorphism in long-chain acyl-CoA dehydrogenase (LCAD) reduces enzyme stability and function

Megan E. Beck, Yuxun Zhang, Sivakama S. Bharathi, Beata Kosmider, Karim Bahmed, Mary K. Dahmer, Lawrence M. Nogee, Eric S. Goetzman

Research output: Contribution to journalArticlepeer-review

Abstract

The fatty acid oxidation enzyme long-chain acyl-CoA dehydrogenase (LCAD) is expressed at high levels in human alveolar type II (ATII) cells in the lung. A common polymorphism causing an amino acid substitution (K333Q) was previously linked to a loss of LCAD antigen in the lung tissue in sudden infant death syndrome. However, the effects of the polymorphism on LCAD function has not been tested. The present work evaluated recombinant LCAD K333Q. Compared to wild-type LCAD protein, LCAD K333Q exhibited significantly reduced enzymatic activity. Molecular modeling suggested that K333 is within interacting distance of the essential FAD cofactor, and the K333Q protein showed a propensity to lose FAD. Exogenous FAD only partially rescued the activity of LCAD K333Q. LCAD K333Q protein was less stable than wild-type when incubated at physiological temperatures, likely explaining the observation of dramatically reduced LCAD antigen in primary ATII cells isolated from individuals homozygous for K333Q. Despite the effect of K333Q on activity, stability, and antigen levels, the frequency of the polymorphism was not increased among infants and children with lung disease.

Original languageEnglish (US)
Pages (from-to)83-89
Number of pages7
JournalMolecular genetics and metabolism
Volume131
Issue number1-2
DOIs
StatePublished - Sep 1 2020

Keywords

  • Fatty acid oxidation
  • Long-chain acyl-CoA dehydrogenase
  • Mitochondria
  • Respiratory distress
  • Type II alveolar pneumocytes

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology

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