Over the past eight years we, along with collaborators Henri Brunengraber (CWRU) and Guofang Zhang (Duke), have published 16 manuscripts detailing the metabolism of 4-hydroxy acids and aldehydes. Likely the most important finding from our work was published in two manuscripts (JBC 2009; JACS 2010) where we showed that the dogmatic lipid peroxidation product, 4-hydroxynonenal (4-HNE) could be metabolized through a novel pathway that involves the recycling of the carbon framework to acetyl-CoA, propionyl-CoA, and formate. Prior to this work, it was generally thought that the fates of 4-HNE consisted of either glutathionylation and excretion, or adduction of proteins and DNA. In a series of five subsequent papers, we were able to prove that the catabolic pathways we discovered are the primary route of disposal of 4-HNE under normal physiologic conditions. Further, we were able to discover that it is only under conditions of impaired β- oxidation that 4-HNE glutathionylation or protein adduction becomes relevant. Going forward our goal is to prove the relevance of this hypothesis in various disease states, and argue for a more fundamental role for LPO in normal physiology, and more clearly define how these ‘normal’ processes are disrupted during disease.

a. Wilson KA, Han Y, Zhang M, Hess JP, Chapman KA, Cline GW, Tochtrop GP, Brunengraber H, Zhang GF. Inter-relations between 3-hydroxypropionate and propionate metabolism in rat liver: relevance to

    disorders of propionyl-CoA metabolism. Am J Physiol Endocrinol Metab. 2017;313, E413-E428. PMID:28634175

b. Sadhukhan S, Han Y, Jin Z, Tochtrop GP*, Zhang GF*. Glutathionylated 4-hydroxy-2-(E)-alkenal enantiomers in rat organs and their contributions toward the disposal of 4-hydroxy-2-(E)-nonenal in rat

     liver. Free Radical Biol Med. 2014;70:78-85. PMID: 4040968.

c. Sadhukhan S, Zhang GF, Tochtrop GP*. Modular isotopomer synthesis of gamma-hydroxybutyric acid for a quantitative analysis of metabolic fates. ACS Chem. Biol. 2014;9:1706-11. PMID: 4136706.

d. Zhang GF, Kombu RS, Kasumov T, Han Y, Sadhukhan S, Zhang J, Sayre LM, Ray D, Gibson KM, Anderson VA, Tochtrop GP, Brunengraber H. Catabolism of 4-hydroxyacids and 4-hydroxynonenal via 4-hydroxy        4-phosphoacyl-CoAs. J Biol Chem. 2009;284:33521-34. PMID: 2785196.