PNAS：美开发出高叶酸含量转基因西红柿
美国研究人员6日表示，他们采用转基因技术，成功地培育出含有人们每日所需的叶酸的转基因西红柿。相关研究结果发表在本周的美国《国家科学院学报》网络版上。
佛罗里达大学植物生物化学家安德鲁.瀚森表示，新的研究成果“将有望让全球人类受益。现在虽然只是在西红柿上取得了成功，但我们能将其应用于欠发达国家的谷物和农作物中，那里（食物中）叶酸不足是十分严重的问题。”瀚森和他的同事耶西•格里高利共同开发出了转基因西红柿。
叶酸是人类身体生长和发育过程中最为重要的营养物质之一，医生建议打算怀孕和已经怀孕妇女的饮食中应该含有丰富的叶酸。因为在人体核苷生产和许多其他基本的新陈代谢过程中，叶酸均具有重要作用。没有它，人体细胞分裂将不可能正常进行。事实上，新生婴儿的生理缺陷和儿童其他发育问题，以及许多成人健康问题如贫血均同缺乏叶酸相关。
类似于菠菜的绿叶菜通常含有维生素，但几乎没有人能摄入足够量的绿叶菜来获得所需的叶酸。于是在1998年，美国食品和药物管理局规定许多谷物产品如大米、面粉和玉米粉必须添加合成叶酸。
研究人员认为，转基因西红柿要获得美国食品和药物管理局的批准还需要数年的时间。而在此之前，还需要完成许多的研究工作，其中包括转基因对西红柿自身带来的影响。此外，研究发现，转基因西红柿中的叶酸量得到提高的同时，植物中另一种化学物质蝶啶的量也在增加。但目前对该化学物质的性质了解甚少，因此研究人员还必须了解和解除它的影响。
Folate biofortification of tomato fruit
Rocío I. Díaz de la Garza*, Jesse F. Gregory, III
, and Andrew D. Hanson*,
Departments of *Horticultural Sciences and Food Science and Human Nutrition, University of Florida, Gainesville, FL 32611
Communicated by Lonnie O. Ingram, University of Florida, Gainesville, FL, January 16, 2007 (received for review October 3, 2006)
Abstract
Folate deficiency leads to neural tube defects and other human diseases, and is a global health problem. Because plants are major folate sources for humans, we have sought to enhance plant folate levels (biofortification). Folates are synthesized from pteridine, p-aminobenzoate (PABA), and glutamate precursors. Previously, we increased pteridine production in tomato fruit up to 140-fold by overexpressing GTP cyclohydrolase I, the first enzyme of pteridine synthesis. This strategy increased folate levels 2-fold, but engineered fruit were PABA-depleted. We report here the engineering of fruit-specific overexpression of aminodeoxychorismate synthase, which catalyzes the first step of PABA synthesis. The resulting fruit contained an average of 19-fold more PABA than controls. When transgenic PABA- and pteridine-overproduction traits were combined by crossing, vine-ripened fruit accumulated up to 25-fold more folate than controls. Folate accumulation was almost as high (up to 15-fold) in fruit harvested green and ripened by ethylene-gassing, as occurs in commerce. The accumulated folates showed normal proportions of one-carbon forms, with 5-methyltetrahydrofolate the most abundant, but were less extensively polyglutamylated than controls. Folate concentrations in developing fruit did not change in controls, but increased continuously throughout ripening in transgenic fruit. Pteridine and PABA levels in transgenic fruit were >20-fold higher than in controls, but the pathway intermediates dihydropteroate and dihydrofolate did not accumulate, pointing to a flux constraint at the dihydropteroate synthesis step. The folate levels we achieved provide the complete adult daily requirement in less than one standard serving.
Tetrahydrofolate (THF) and its derivatives (folates) are essential cofactors in one carbon transfer reactions in almost all organisms, being required for synthesis of glycine, serine, methionine, purines, and thymidylate (1, 2). Plants and microorganisms are able to synthesize folates, but humans lack this capacity and require a dietary supply. Folates in human diets come mainly from plant foods (2). However, many plants, including tubers, cereals, and most fruits contain far less folate than green leafy vegetables, the best source (2, 3).
Folate deficiency is a worldwide health problem associated with spina bifida and other birth defects, megaloblastic anemia, cardiovascular diseases, and some cancers (4–7). Currently, the United States and other western countries mandate fortification of grain products with synthetic folic acid to help their populations reach the recommended dietary allowance, which is 400 µg/day for adults and 600 µg/day for pregnant women (5, 8). However, food fortification can be difficult to implement in developing countries due to recurrent costs, distribution inequities, and lack of an industrial food system (9). In these areas, folate deficiency causes at least 200,000 severe birth defects every year (10). In addition, epidemiological data suggest that folate malnutrition is the main cause of anemia in at least 10 million pregnant women in developing countries (11, 12). Moreover, concerns have arisen about the effects of chronic exposure of western populations to synthetic folic acid (7, 13, 14). Such concerns are based primarily on the ability of folic acid, at high levels of intake, to bypass the usual physiological control of folate distribution and metabolism, causing entry of unreduced folic acid into the systemic circulation. Consequently, dietary tetrahydrofolates are predicted to have a higher margin of safety. Folate enhancement in plant foods (biofortification) through metabolic engineering therefore represents an attractive alternative strategy to increase the intake of natural folates in rich and poor countries alike (2, 15, 16).
Folates are tripartite molecules consisting of pteridine, p-aminobenzoate (PABA), and glutamate moieties usually with a short, 
-linked chain of additional glutamates attached to the first glutamate (Fig. 1A). Folate biosynthesis in plants is highly compartmentalized, with pteridines synthesized in the cytosol and PABA produced in plastids. These moieties are condensed in mitochondria forming dihydropteroate, which is glutamylated to form folates (Fig. 1B). Previous engineering work in tomato fruit and Arabidopsis involved the overexpression of GTP cyclohydrolase I (GCHI) (17, 18), which catalyzes the first committed step of pteridine biosynthesis (Fig. 1B) (19). Although GCHI overexpression greatly increased the flux to pteridines, folate levels were raised only 2- to 4-fold (17, 18). This modest increase in folate was associated with severely depleted PABA pools in the engineered plants, suggesting that the PABA supply had become limiting for folate synthesis (17). This problem was successfully addressed in the present study by engineering PABA production in ripening tomato fruit, and combining this trait with pteridine overproduction. This work demonstrates the feasibility of developing crops with enough folate to supply the adult recommended dietary allowance in a single standard serving (100 g/serving). It also sheds light on the control of the folate biosynthesis pathway in plants.
Fig. 1. Structure and biosynthesis of folates. (A) Chemical structure of THF, monoglutamyl form. Plant folates have -linked polyglutamyl tails of up to approximately six residues attached to the first glutamate. One-carbon units at various levels of oxidation are attached to N-5 and/or N-10. The pteridine ring of folates and free pteridines can exist in tetrahydro-, dihydro-, and fully oxidized forms. (B) The plant folate biosynthesis pathway. Pteridines are in blue. PABA and its precursor aminodeoxychorismate (ADC) are in green. Red arrows are the engineered GTP cyclohydrolase I (GCHI) and ADC synthase (ADCS) reactions. Asterisks show two possible constraints in the pathway in engineered fruit (pteridine transport and phosphorylation). DHN, dihydroneopterin; -P, monophosphate; -PP, pyrophosphate -PPP, triphosphate; DHM, dihydromonapterin; HMDHP, hydroxymethyldihydropterin.
英文全文链接：http://intl.pnas.org/cgi/content/full/104/10/4218
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