식물에서 인체와 유사한 N-glycan 구조를 가진 당단백질 생산에 대한 최근 연구동향 = Recent Studies on the Production of Glycoproteins Containing Humanized N-glycan Structures in Plants

다국어 초록 (Multilingual Abstract)

Several host systems including mammalian cells, yeasts, plants, bacteria, insects and transgenic animals have been employed to produce recombinant therapeutic glycoproteins. Among them, plant system has many advantages such as the low cost, animal pathogens-free, eco-friendly production, and ease of scale up. However, plants are unable to perfectly synthesize human-type N-glycans of therapeutic glycoproteins. It could represent a severe limitation on the use of therapeutic glycoproteins produced from transgenic plants. In this article, we focus on the importance of N-glycosylation, the advantage of molecular farming and its progress strategies, the difference of N-glycan structure between animals and plants, the risk of potential immunogenicity of plant glycoproteins, the strategies to reduce the potential immunogenicity by N-glycosylation engineering including endoplasmic reticulum (ER) targeting of therapeutic glycoproteins, the inhibition of plant-specific glycosyltransferases, and the expression of human specific glycosyltransferases to synthesis galactosylated and sialylated N-glycans in plants.

국문 초록 (Abstract)

1989년에 처음으로 형질전환식물체를 이용하여 재조합 항체가 생산된 이래로(Hiatt et al., 1989) 분자농업 및 관련 기술들은 매우 빠르게 발전해왔다. 식물 시스템을 이용하여 의료용 단백질 및 산업용 소재 등의 생산은 경제성 및 안전성 측면에서 동물세포 시스템 보다 우위에 있으며, 단점으로 남아있는 낮은 발현양, 재조합 당단백질 내 식물특이 당쇄구조의 존재로 인한 면역성 문제 및 동물 N-glycan 내 존재하는 당쇄구조의 결핍으로 인한 생체 내 안전성의 부족 등의 문제점들이 생명공학기술의 발달에 의해 현재 빠르게 극복해 나가고 있는 실정이다. 그러나 국내의 식물특이 당쇄구조 제어 기작 및 발현 연구는 아직 초기 단계에 있다. 모델 식물(애기장대)의 기초 유전자 연구와 당쇄 구조분석에 대한 기술은 확보되어 있으나 아직 외국의 선두 연구진과의 격차는 크다고 할 수 있다. 전세계적으로 많은 연구들을 통해 식물특이 당쇄구조인 α1,3-fucose, β1,2-xylose 및 Lewis-a epitope의 생합성을 제어할 수 있는 기술들이 확립되었고, α1,6-fucose나 β1,4-galactose와 같은 식물 N-glycan 내에 존재하지 않는 당쇄구조를 첨가하는 것도 가능해졌다. 최근 전세계적으로 활발하게 수행되고 있는 식물체 내에 sialic acid를 생합성하기 위한 대사 경로도 관련 효소들 및 transporter들의 연구 및 도입에 의해 구축되어가고 있다. 따라서 멀지 않은 미래에 인체와 동일한 N-glycan 구조를 가지는 당단백질을 대량 생산하는 식물체의 개발이 이루어질 것으로 전망되고, 유용 유전자의 형질전환을 통해 의료용 및 산업용 소재 개발에 활용됨으로써 장기적으로 동물세포배양 시스템을 대체할 수 있는 기술로 발전할 수 있을 것으로 기대된다. 이러한 인간화 당단백질을 생산하는 모델식물 시스템을 이용하여 고부가가치의 의약품 및 산업용 소재를 생산하는 분자농업 분야는 프로모터 연구를 통한 고발현 기술, 대사공학 관련 기술, 목적하는 세포 소기관으로의 집적 및 정제기술 등과 융합하여 미래의 바이오산업의 발전을 위한 핵심기술로 발전할 것으로 전망된다.

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