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Bulku A, Weaver TM, Berkmen MB. Biochemical Characterization of Two Clinically-Relevant Human Fumarase Variants Defective for Oligomerization. Open Biochem J. 2018;12:1-15doi: 10.2174/1874091X01812010001.
Bulku, A., Weaver, T. M., & Berkmen, M. B. (2018). Biochemical Characterization of Two Clinically-Relevant Human Fumarase Variants Defective for Oligomerization. The open biochemistry journal, 121-15. https://doi.org/10.2174/1874091X01812010001
Bulku, Artemisa, et al. "Biochemical Characterization of Two Clinically-Relevant Human Fumarase Variants Defective for Oligomerization." The open biochemistry journal vol. 12 (2018): 1-15. doi: https://doi.org/10.2174/1874091X01812010001
Bulku A, Weaver TM, Berkmen MB. Biochemical Characterization of Two Clinically-Relevant Human Fumarase Variants Defective for Oligomerization. Open Biochem J. 2018 Jan 29;12:1-15. doi: 10.2174/1874091X01812010001. eCollection 2018. PMID: 29456767; PMCID: PMC5806193.
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Open Biochem J. 2018 Jan 29;12:1-15. doi: 10.2174/1874091X01812010001. eCollection 2018.

Biochemical Characterization of Two Clinically-Relevant Human Fumarase Variants Defective for Oligomerization.

The open biochemistry journal

Artemisa Bulku, Todd M Weaver, Melanie B Berkmen

Affiliations

  1. Department of Chemistry and Biochemistry, Suffolk University, 8 Ashburton Place, Boston, MA, USA.
  2. Department of Chemistry and Biochemistry, University of Wisconsin-La Crosse, La Crosse, WI, USA.

PMID: 29456767 PMCID: PMC5806193 DOI: 10.2174/1874091X01812010001

Abstract

BACKGROUND: Fumarase, a significant enzyme of energy metabolism, catalyzes the reversible hydration of fumarate to L-malate. Mutations in the

METHODS: We constructed two variants of hexahistidine-tagged human recombinant fumarase, A308T and H318Y, associated with FHD and HLRCC, respectively. Both Ala308 and His318 lie within the fumarase intersubunit interface. We purified unmodified human fumarase and the two variants, and analyzed their enzymatic activities and oligomerization states

RESULTS: Both variants showed severely diminished fumarase activity. Steady-state kinetic analysis demonstrated that the variants were largely defective due to decreased turnover rate, while displaying K

CONCLUSION: We conclude that A308T and H318Y render human fumarase enzymatically inactive via defective oligomerization. Therefore, some forms of FHD and HLRCC can be linked to improperly folded quaternary structure.

Keywords: Fumarase; Fumarate hydratase; Fumarate hydratase deficiency; Fumaric aciduria; Hereditary leiomyomatosis; Renal cell cancer

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