Skip to Main Content
 

Global Search Box

 
 
 

ETD Abstract Container

Abstract Header

Interrelations Between 3-Hydroxypropionate, Propionate, And ß-Alanine Metabolism: Relevance To Propionic Acidemia

Wilson, Kirkland A, Wilson
http://rave.ohiolink.edu/etdc/view?acc_num=case1515518969675728

Abstract Details

, Doctor of Philosophy, Case Western Reserve University, Nutrition.
Propionic acidemia (PA) and methylmalonic acidemia (MMA), both disorders of propionyl-CoA metabolism, are both diseases of toxic compound accumulation. Propionate, 3-hydroxypropionate (3HP), methylcitrate, methylmalonate, related compounds, and ammonium accumulate in body fluids of patients. Although liver transplant alleviates hyperammonemia, high concentrations of toxic compounds persist in body fluids. We hypothesized that metabolic perturbations result from the simultaneous presence of propionate and 3HP in body fluids. We then confirmed this hypothesis and detailed our findings. First, in the perfused rat liver, propionate and 3HP result in major overload of the citric acid cycle (CAC) and large perturbations in CAC metabolite ratios. Second, energy homeostasis is greatly perturbed; [ATP]/[ADP] and [ATP]/AMP] ratios were decreased while total adenine nucleotide pool was increased, thus the overloaded CAC doesn’t supply enough reducing equivalents to maintain adenine nucleotide homeostasis. Third, there is major CoA trapping in propionyl-CoA, methylmalonyl-CoA, and succinyl-CoA and tripling of total CoA concentration. Further, we identified new fates of propionate and 3HP metabolism in perfused rat livers, plasma samples from heterozygous and conditional knockout mice of PA and MMA, and plasma samples from MMA and PA patients. Propionate and 3HP form nephrotoxic maleate via independent processes not involving the CAC. Propionate conversion to maleate likely occurs by propionyl-CoA metabolism to cytosolic methylmalonyl-CoA then further conversion to maleate by unknown processes. This has clinical relevance to the high occurrence of renal failure in MMA and the increased rate of renal failure in PA post-orthotopic liver transplant. Lastly, we identified new metabolic fates of the 3HP metabolite, ß-alanine. We showed that ß-alanine (i) stimulates CoA synthesis but does not directly contribute to the ß-alanine moiety of CoA, (ii) reversibly forms 3HP and forms the novel metabolite 2-(aminomethyl)-malonate by carboxylation via pyruvate carboxylase, and (iii) perturbs neurotransmitter balance. These discoveries were made in perfused rat livers and in live rats using a combination of metabolomics and stable isotope techniques. Overall, research into disorders of propionyl-CoA metabolism is a complex area of investigation. We explored propionyl-CoA metabolism in the setting of these disorders and report findings that have implications for the clinical management of these patients.
Henri Brunengraber (Advisor)
Danny Manor (Committee Chair)
Michelle Puchowicz (Committee Member)
George Dubyak (Committee Member)
Gregory Tochtrop (Committee Member)
Shawn McCandless (Committee Member)
Douglass Kerr (Committee Member)
Biochemistry; Nutrition

Recommended Citations

Citations

  • Wilson, Wilson, K. A. (n.d.). Interrelations Between 3-Hydroxypropionate, Propionate, And ß-Alanine Metabolism: Relevance To Propionic Acidemia [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1515518969675728

    APA Style (7th edition)

  • Wilson, Wilson, Kirkland. Interrelations Between 3-Hydroxypropionate, Propionate, And ß-Alanine Metabolism: Relevance To Propionic Acidemia. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1515518969675728.

    MLA Style (8th edition)

  • Wilson, Wilson, Kirkland. "Interrelations Between 3-Hydroxypropionate, Propionate, And ß-Alanine Metabolism: Relevance To Propionic Acidemia." Doctoral dissertation, Case Western Reserve University. Accessed MAY 05, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=case1515518969675728

    Chicago Manual of Style (17th edition)

case1515518969675728
484
© , all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.