Optimizing therapy for argininosuccinic aciduria

Abstract

Argininosuccinic aciduria (ASA) is a urea cycle disorder with a complex phenotype. In spite of a lower risk for recurrent hyperammonemic episodes as compared to the proximal disorders of ureagenesis, subjects with ASA are at risk for long-term complications including, poor neurocognitive outcome, hepatic disease and systemic hypertension. These complications can occur in spite of current standard therapy that includes dietary modifications and arginine supplementation suggesting that the presently available therapy is suboptimal. In this article, we discuss the natural history of ASA and the recent mechanistic insights from animal studies that have shown the requirement of argininosuccinate lyase, the enzyme deficient in ASA, for systemic nitric oxide production. These findings may have therapeutic implications and may help optimize therapy in ASA.

Copyright © 2012 Elsevier Inc. All rights reserved.

Figures

Figure 1. The urea cycle and the citrulline-nitric oxide cycle

In the liver, ASS and ASS are involved in ureagenesis whereas in most other tissues, they are required for endogenous arginine synthesis. The production of nitric oxide is coupled within this Citrulline-NO cycle. NAGS: N-acetyl glutamate synthase; CPS1: Carbamoyl phosphate synthase 1; OTC: Ornithine transcarbamylase; ASS: Argininosuccinate synthase; ASL: Argininosuccinate lyase; ARG: Arginase 1; NOS: Nitric oxide synthase. Reproduced with permission from publishers John Wiley and Sons.

Figure 2. The catalytic and structural functions of ASL

ASL is not only required for endogenous arginine synthesis (a catalytic function), but is strcuturally required to maintain a complex that facilitates chanelling of exogenous arginine to nitric oxide synthase (NOS) for Nitric oxide (NO production). The tetrameric ASL enzyme depicted in green represents that which is required for catalysis while the region in gray is needed for the NO-synthesis-complex that includes SCL7A1, the cationic arginine transporter.