Interaktion des NaDC3 und des NaCT mit Carbaglu, einem Medikament zur Behandlung der Hyperammonämie

Interaktion des NaDC3 und des NaCT mit Carbaglu, einem Medikament zur Behandlung der Hyperammonämie

Interaction of Carbaglu, a drug for treating hyperammonemia, with the transporters NaDC3 and NaCT

Elisabeth Schwob

Doctoral thesis

Date of Examination: 2017-12-05

Date of issue: 2017-10-27

Advisor: Burckhardt, Birgitta-Christina Prof. Dr.

Referee: Burckhardt, Birgitta-Christina Prof. Dr.

Referee: Asif, Abdul Rahman Prof. Dr.

Persistent Address: http://hdl.handle.net/11858/00-1735-0000-0023-3F49-5

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Abstract

English

Primary or secondary N-acetylglutamate synthase (NAGS) deficiency leads to the reduction of N-acetylglutamate (NAG), the natural activator of the urea cycle. It results in hyperammonemia. Hyperammonemic crises can be life-threatening. Carbaglu administered orally can normalize elevated blood ammonia levels. Its active agent N-carbamoylglutamate (NCG), a structural and stabile analog of NAG, can reactivate the urea cycle. The renal clearance of NCG suggests active renal secretion. NCG was identified as a high-affinity substrate of the sodium-dependent dicarboxylate transporter NaDC3. The addition of NCG to Xenopus oocytes expressing human NaDC3 protein during two-electrode voltage clamp experiments conducted a sodium-dependent inward current with a Michaelis-Menten constant (Km) around its plasma level. As the transporter is found on the basolateral membranes in renal proximal tubule cells it can be therefore assumed that it mediates the first step of glomerular secretion of NCG. In NaCT-expressing oocytes NCG did not induce measurable currents.

Keywords: hyperammonemia; N-acetylglutamate synthase; Carbaglu; N-carbamylglutamate; urea cycle disorders; NaDC3; SLC13A3; SLC13A5; NaCT