TY - JOUR
T1 - The common K333Q polymorphism in long-chain acyl-CoA dehydrogenase (LCAD) reduces enzyme stability and function
AU - Beck, Megan E.
AU - Zhang, Yuxun
AU - Bharathi, Sivakama S.
AU - Kosmider, Beata
AU - Bahmed, Karim
AU - Dahmer, Mary K.
AU - Nogee, Lawrence M.
AU - Goetzman, Eric S.
N1 - Funding Information:
This work was supported by R01 DK090242 (E.S.G.), R01 HL118171 (B.K.) and the Catalyst Award from the American Lung Association (K.B.).
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - 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.
AB - 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.
KW - Fatty acid oxidation
KW - Long-chain acyl-CoA dehydrogenase
KW - Mitochondria
KW - Respiratory distress
KW - Type II alveolar pneumocytes
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U2 - 10.1016/j.ymgme.2020.04.005
DO - 10.1016/j.ymgme.2020.04.005
M3 - Article
C2 - 32389575
AN - SCOPUS:85084381336
SN - 1096-7192
VL - 131
SP - 83
EP - 89
JO - Molecular genetics and metabolism
JF - Molecular genetics and metabolism
IS - 1-2
ER -