麴酸是一種由絲狀真菌所代謝產生的有機酸，因為麴酸具有某些特殊的生物性質，所以常被的應用在許多用途上，例如其衍生物可當成止痛劑、殺蟲劑、食品添加劑。近年來，麴酸因具有抑制黑色素生成的能力，所以於美白保養品中被大量使用。有鑑於麴酸的廣泛使用性，如何大規模生產麴酸，以符合需求成為一個重要課題。本研究即是以大量生產麴酸為目標，選用米麴菌當作生產菌株，進行菌種改良、培養基設計與發酵生產等相關研究，希望能開發出一個優良的麴酸發酵程序。
在菌種改良的研究上，利用結合原生質體化與誘變的方式，對原始菌株Aspergillus oryzae ATCC 22788 進行改造，以提高麴酸生產能力。經過三回的改良與篩選，高麴酸生產株M3B9被挑選出為後續研究麴酸生產的菌株。M3B9的麴酸生產能力為原始菌株的64倍。另外，兩這在細胞生長、碳源接受度與生長環境pH都有明顯不同，不過M3B9在經過多次繼代培養後，這些特異性會逐漸消失，轉變恢復為原始株。
當獲得優良的生產株時之後，以營養源篩選和回應曲面法尋求合適的培養基。經由6種氮源和7碳源培養測試，在考量產率、發酵方便性、成本等因素後，選擇酵母菌萃取物與蔗糖做為氮、碳源之培養基。接續以回應曲面法討論合適的培養基濃度，當蔗糖濃度為100~130 g/L，酵母菌萃取物濃度為2~5 g/L時，米麴菌的麴酸生產量約可達50 g/L，為原始培養基的1.6倍。
經過菌種改良和培養基的篩選之後，接下來以攪拌氏生物反應器培養，討論改良菌株M3B9麴酸大量生產的可行性。在批次培養研究中，利用三種不同的培養基當成營養源進行M3B9的麴酸發酵生產，在發酵槽中，其麴酸生產情形大致與搖瓶相同。但是在饋料批次實驗中，麴酸生產速度於發酵後期卻會大幅降低。而利用重複批次的培養，則在75 %體積的發酵液更換下，有最好的生產效率，麴酸生產速度類似於批次培養，大約為5 g/L-day。上述麴酸生產的結果，可應用於發酵規模放大之研究，及日後進行大規模的麴酸量產之參考。

Kojic acid is a highly valuable compound, which is commonly produced by filamentous fungi and has wide applications in several fields due to its special biological functions. Because of its wide applications, there is an urgent need for the production of kojic acid on an industrial scale. This study concerns the development of fermentation process including strain improvement, medium design and fermentation operation for mass kojic acid production
Strain improvement, combing induced mutation and protoplasting were applied to improve the wild type strain Aspergillus oryzae ATCC 22788 for high kojic acid production. From the three rounds of strain improvement, we obtained the best kojic acid hyper-production strain M3B9 that could produce kojic acid at level of 32 g/L in shake flask fermentation, which was 64-fold higher than productivity by the wild strain. Besides, wild type and improved strain showed significant differences in terms of byproducts, cell growth, and uptake of carbohydrates. However, gradual decay of specificity indicated that phenotype of M3B9 was not stabile when serially subcultured.
After strain improvement, culture medium screening and optimization was carried out for promoting high kojic acid production. Sucrose and yeast extract were found to be the better candidates for use as carbon and nitrogen sources in the medium for high kojic acid productivity, cell morphology and cost. Through the use of response surface methodology (RSM), the optimal sucrose (100~130 g/L) and yeast extract (2~5 g/L) were identified and used in culture medium.
The study also focused on the feasibility of large scale kojic acid production by using bioreactor. Similar productivity was shown in stirred tank fermentor as well in shake flask. Batch culture demonstrated that M3B9 has the potential for large scale kojic acid production. In order to improve the efficiency of kojic acid fermentation, fed-batch and repeated-batch cultures were performed. Despite accumulation of high concentration of kojic acid at the end of fed-batch culture, productivity decreased markedly during late fermentation period. Repeated-batch culture with 75 % medium replacement revealed the better productivity similar to batch culture. These results suggested that strain improvement, optimal medium design and suitable fermentation strategies can enhance the kojic acid production and can successfully applied for its industrial scale production .

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