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Journal of Endotoxin Research
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Liver argininosuccinate synthase binds to bacterial lipopolysaccharides and lipid A and inactivates their biological activities

Motonobu Satoh

Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa, Japan,moto-sth{at}pharm.teikyo-u.ac.jp

Tsuguya Iwahori

Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa, Japan

Naoki Sugawara

Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa, Japan

Masatoshi Yamazaki

Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa, Japan

The liver is known to clear and detoxify circulating lipopolysaccharide (LPS). To characterize the molecules involved in this process in the liver, we attempted to purify mouse liver protein(s) that can interact with lipid A, a biologically active portion of LPS. By partially purifying the inactivating activity against a synthetic lipid A analog, we observed the enrichment of a 45-kDa protein in the active fractions. The internal amino acid sequences of the protein were identical with those of argininosuccinate synthase (EC 6.3.4.5). To examine whether argininosuccinate synthase can interact with lipid A, we purified the enzyme from mouse liver and found the co-elevation of the specific enzyme activity and specific lipid A-inactivating activity, indicating that argininosuccinate synthase is the major lipid A-interacting protein in liver. Argininosuccinate synthase also inhibited the biological activities (macrophage activation and Limulus test) of natural lipid A and rough-type LPS but not smooth-type LPS. The enzyme activity was inhibited by lipid A and rough-type LPS and also by smooth-type LPS. Native gel electrophoresis of a mixture of argininosuccinate synthase and LPS and immunoprecipitation of a mixture of argininosuccinate synthase and [3H]-LPS with anti-argininosuccinate synthase antiserum showed that argininosuccinate synthase stably bound lipid A and LPS. These findings, together, indicate that argininosuccinate synthase can effectively bind LPS in the liver.

Key Words: Argininosuccinate synthase • clearance • endotoxin • lipid A • liver

Journal of Endotoxin Research, Vol. 12, No. 1, 21-38 (2006)
DOI: 10.1177/09680519060120010301
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