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1 국내외바이오화학동향 Prof. Sunghoon Park Pusan National University, Busan, Korea July 02, 2015 제 1 회 Korea BIOplus+: 바이오화학포럼

2 Outline 서론 : definitions Industrial Biotechnology and Biorefinery Bioenergy vs. Biochemicals 원료 무엇을생산할것인가? 어떻게생산할것인가? 3-hydroxypropionic acid Major tools Conclusion

3 바이오매스기반경제시대도래는 mega trend?? Key drivers: Global warming, 원유가격상승 ( 및유한한매장량 ), 경제성 바이오매스기반경제 바이오매스확보 전처리 / 당화 Sugar platform 구축 미생물공학 / 발효기술 고효율에너지화기술 화학제품 플라스틱 의약품 화장품 전자소재 전환 석유자원기반경제 바이오에탄올 바이오부탄올 바이오디젤 바이오오일 바이오가스

4 Industrial Biotechnology vs. 바이오화학산업 산업바이오기술 (Industrial Biotechnology) : 제품을산업적으로생산하는데있어서재생가능한바이오원료를사용하거나생산공정에서효소나미생물을이용하는기술 (EuropaBio, 2003; US ITC, 2008). 바이오화학산업 : 바이오매스를원료로사용하거나생산공정에서효소나미생물을이용하여화학제품을제조하는산업 바이오매스 (Biomass) : 전분, 설탕, 목재류, 미세조류, 식물유등재생가능한 ( 식물 ) 자원 ( 김용환, 광운대학교 )

5 Fuel vs. Chemicals

6 산업 BT 의제품계통도 : 무엇을생산할수있는가?

7 Biorefinery 원료 : Biomass

8 Starch Biomass (1 세대바이오매스 ) 국내디젤사용량의 5% 대체를위한바이오디젤생산용필요경작지 문제점 Rape seed 식량자원을에너지원으로??? 절대량부족과윤리적문제!! ( 이진원, 서강대학교 )

9 Cellulosic Biomass (2 세대바이오매스 ) What it is? 문제점 국내부존자원부족 전처리기술낮은당수율 ( 이진원, 서강대학교 )

10 What it is? Algal Biomass (3 세대바이오매스 ) 문제점 경제적 Biomass 생산 낮은태양광에너지전환효율 수확기술 ( 이진원, 서강대학교 )

11 Microalgae Production and Utilization (ABC 사업단, 2015)

12 4 세대 ( 바이오매스 ) 원료 - 모든탄소?? 유기성폐자원 석탄, 천연가스등지하자원 산업체및발전소부생가스 메탄, CO 2 등 탄소자원화기술 : C1 가스이용바이오리파이너리및생물학적 Fischer-Tropsch 공정??? ( 이진원, 서강대학교 )

13 Target: 무엇을생산할것인가? 학계 ( 대학, 연구소 ): What is new? Scientific interest. 회사 : 상업적생산, 주력제품과의연계성, Intellectual property 국가 : 산업생태계 ( 국가전후방사업과의연계효과 )

14 대체원료 (Chemical Feedstock) US DOE report 대체원료 (Feedstock) 개발대상대체화학물질의선정 - 30 개의잠재적인후보군선정 -> 12 개의기본요소 (building block) 최종선정 - 후보물질을대상으로유도체들의시장성과합성방법의기술적인복잡성을고려 12 가지대체화학물질의분류 ( 탄소의수기준 ) 탄소수대체화학물질탄소수대체화학물질 hydroxypropionic acid 글리세롤 3-ydroxy butyrolactone 아스파탐산 1,4 이염기산 ( 숙신산, 푸마르산, 사과산 ) 5 6 이타콘산 레블리닉산 자일리톨 / 아라비톨 2,5 푸란디카르복실산 글루카릭산 5 글루타민산소르비톨

15 Biological and chemical routes for the 2004 DOE's top 12 chemicals and the revised 2010 top 10 chemicals from biomass. SY Lee s group, Met. Eng. 2015

16 중요화합물상업화진행상황 ( 산업원천기술개발기획, 2014; DSM)

17 Overview of the commercial production of top bio-based chemicals Platform chemical Derivatives Commercial status Company Ethanol Polyethylene (PE) Commercialized Braskem Mono-ethylene glycol Commercialized DOW chemical, Mitsui Chemicals, India Glycols Ltd and Green col Taiwan Corporation Polypropylene Commercialized Braskem and Novozyme Acetic acid Commercialized Wacker Polyethylene terepthalic acid (PET) Preparing commercialization Gevo, Toray, Virent and PTC group Glycerol Epichlorohydrin Commercialized Solvay and Dow chemical Propylene glycol Commercialized ADM, Dow chemical, Ashland and Cargill Acrylic acid Preparing commercialization Arkema and Nippon shokubai Glycerol carbonate Commercialized untsman 3-ydroxypropionic acid Acrylic acid Preparing commercialization Perstorp, BASF, Cargill, Novozymes, Opxbio, Dow chemical and Metabolix Lactic acid Acrylic acid Preparing commercialization Myriant Poly lactic acid (PLA) Commercialized Purac-Toyobo, Futerro and NatureWorks LLC Succinic acid 1,4-butanediol Preparing commercialization Myriant, Jhonson Matthey Davy technologies, BioAmber, Dupont and Reverdia Tetrahydrofuran (TF) Preparing commercialization Myriant, Jhonson Matthey Davy technologies, BioAmber and Dupont Gamma-butyrolactone Preparing commercialization BioAmber and Dupont Poly butylene succinate Preparing commercialization BioAmber, Reverdia, PTTMCC and Sinopec Biopolymers Poly butylene succinate Commercialized Myriant and Showa Denko K.K. Polyester polyols Preparing commercialization Myriant, BioAmber and Reverdia Furfural Furfuryl alcohol International furan chemicals, Shijazhuang worldwide furfural and furfuryl alcohol and furan resin Co. Commercialized Ltd Itaconic acid Poly itaconic acid Commercialized Itaconix corporation Methyl methacrylate Preparing commercialization Lucite international, Mitsubishi rayon, Evonik and many companies. Isoprene Preparing commercialization DuPont, Goodyear, Amyris, Braskem, Michelin, Ajinomoto and Bridgestone Levulinic acid Commercialized Avantium Preparing commercialization Segetis and Biofine Technology Xylitol Commercialized Danisco 2,5-Furandicarboxylic acid Poly ethylene furandicarboxylic acid Preparing commercialization Avantium, Danone and ALPA Polyamide Preparing commercialization Avantium and Solvay Glucaric acid Adipic acid Preparing commercialization Rennovia and Rivertop renewables MF Preparing commercialization AVA Biochem Sorbitol Isosorbide Commercialized Roquette and ADM Farnesene Commercialized Amyris (SY Lee s group, 2015, Met. Eng 28:223)

18 국내주요기업의 IBT 추진현황 바이오기업 CJ 제일제당 : 아미노산, Nylon 4, PLA, BDO, diamine 등 대상 : PLA, Nylon 4, 아미노산 백광 : diamine, 아미노산 화학기업 LG 화학 : PLA 호남석유화학 : PET, PLA 제일모직 : nylon, PLA GS Caltex: BDO, n-butanol, Nylon 4 SK Energy: n-butanol, Biodiesel 삼양사 : PLA, Isosorbide 코오롱 : nylon 4 삼성정밀화학 : PBS(Polybutylene succinate), PBT(Polybutylene terephthalate) 삼성석유화학 : PDO, BDO 삼성종합기술원 : 3-P, BDO (2011, 지식경제부자료수정 )

19 국내주요대학 / 연구소의바이오화학추진현황 Amino acids: KAIST, 고려대 Lactic acid: 광운대, 화학연구원, 한국외대, 전남대 PDO: 생명공학연구원, KIST, 화학연구원 BDO: 서울대, 서강대, 고려대, KAIST 3-P: 부산대, 서울대, 포항공대 Succinic acid: KAIST Diacids (long chain): 이화여대, 생명공학연구원, 건국대 Diamine: KAIST, 홍익대 자일리톨 : 서울대, KAIST isoprenoids: 경상대 목질계전처리 : 화학연구원, 공주대, 단국대, 경희대, 광운대 에탄올 : 서울대, 고려대 부탄올 : KAIST, 화학연구원 Biohydrogen: 한국해양연구원, 에너지기술연구원부산대, 포항공대, 서강대 Advanced biofuels: KAIST, 서울대, 고려대 Microalgal culture: KAIST, 인하대, 경북대, 고려대, 에너지기술연구원, 충남대 (2011, 지식경제부자료수정 )

20 Method: 어떻게생산할것인가? Biomass 생산 Biomass 원료전처리 미생물촉매개발 : Pathway engineering Enzyme engineering Bio-process development (Bio-reaction engineering) Down-stream processing (Separation and purification) Chemical conversion (and polymerization)

Importance of 3-P 2 C O O N 2 O O Ethyl ethoxy

Global market - 4 million ton per year 3.

Malonic acid 3 C C 3 O 1,3-Propanediol O

21 Importance of 3-P 2 C O O N 2 O O Ethyl ethoxy propionate (EEP) O Acrylamide O 3-P O O O O Poly-3-P O O O n 1. Top 3rd platform chemical by US- DOE 2. Global market - 4 million ton per year 3. The market price is ~1,300 US$/ton. 4. Estimated to be >$10B. O O n R O O Acrylic esters O Acrylic acid Malonic acid 3 C C 3 O 1,3-Propanediol O Acrylic polymers Source: Top Value Added Chemicals From Biomass, PNNL & NREL, 2004; Chemical market reporter; ICIS Pricing 21

glycerol; Pathogenic Pseudomonas denitrificans Naturally produce coenzyme B 12 (+O 2 condition) Cannot grow on

22 Development of 3-P production strains Escherichia coli Cannot synthesize B 12 Easy to handle; Genetic tool box well developed Klebsiella pneumoniae Naturally produce coenzyme B 12 ( O 2 condition) Efficiently utilize glycerol; Pathogenic Pseudomonas denitrificans Naturally produce coenzyme B 12 (+O 2 condition) Cannot grow on glycerol Malonyl-CoA reductase pathway Non-pathogenic, new K. pneumoniae isolate Genome of new P. denitrificans isolate 22

Challenges in 3-P production Glycerol 3-P Byproducts Cell growth Pathway enzymes DhaB/GdrAB ALD Activity, stability, enzyme inhibition Cofactor Coenzyme B 12 (NAD + ) Synthesis, regulation Tolerance

23 Challenges in 3-P production Glycerol 3-P Byproducts Cell growth Pathway enzymes DhaB/GdrAB ALD Activity, stability, enzyme inhibition Cofactor Coenzyme B 12 (NAD + ) Synthesis, regulation Tolerance 3-P Byproducts Transporters, chaperones, adaptive evolution Physiology/Fermentation Cell growth Carbon metabolism Pathway Engineering Process optimization Commercially feasible process: Titer, Rate and Yield??

24 DhaB and ALD were not stable Ashok et al (2011) Meta. Eng. 15: 10-24

25 Toxic effect of 3-P ydroxypropanoic acid concentration (mm) Glycerol consumed x 0.5 (mm) OD (600 nm) x 10 3-P (mm) 1,3-PDO (mm)

26 LysR family transcriptional regulator A LysR LysR RS AS P B RS RNAP AS P C Inducer (eg. 3-P) RS AS RNAP P LysR family transcriptional regulator can positively regulate target gene transcription

27 Expression control could stabilize enzyme activities and improved 3-P production Relative 3-P titer P Cell mass Time (h) Relative cell mass DhaB (U/mg protein) A Time (h) DhaB KGSAD KGSAD (U/mg protein) Medium copy plasmid; Strong promoters; igh gdrab expression; K igh Titer, Rate and Yield were achieved. Enzyme activities were maintained at desired levels. 27

28 Tools in Metabolic Engineering: Synthetic Biology Basic parts (or resistors, transistors, etc) in biology, should be the building blocks or pieces of DNA that are needed to translate a gene.

Gene expression optimization: Synthetic promoter and BCD Promoter GFP (a.u) RFP (a.u) RFP/ GFP P1 463.87 1489.77 3.21 P2 117.45 758.61 6.46 P3 634.54 1419.27 2.24 P4 57.63 173.77 3.02 P5 546.55 1341.

29 Gene expression optimization: Synthetic promoter and BCD Promoter GFP (a.u) RFP (a.u) RFP/ GFP P P P P P P P P P P P P P P (Mutalik et al, Science, 2013)

30 UTR Engineering GFP RFP 정규열, 포항공대

31 Tools in Metabolic Engineering: Genome Engineering λ Red recombinase omologous recombination MAGE (Multiplex Automated Genome Engineering) Antisense RNA CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)

32 CRISPR Applications of CRISPR-Cas9 CRISPR-Cas9: DNA complex Sander, Jeffry D., and J. Keith Joung. Nature Biotechnol 32.4 (2014):

33 For success of biorefinery, collaboration and integration will be important We need a clever combination of biological and catalytic processes to produce the diversity of chemical precursors currently used by the chemical industry. This requires collaboration between biochemical engineers and reaction engineers/traditional catalysis engineers. Courtesy of T. Good (NSF)

34 But ultimately, we will need alternative feedstocks for the biological processes Chemical/catalytic conversion of lignocellulosic/algal biomass to a fermentable feedstock other than glucose Engineering whole plant, to make lignocellulosic material easier to degrade without harming plant fitness Mass micro-algal production Examination of other feedstocks (methane, CO 2, organic wastes) for the fermentation

35 Contributors (3-P) Dr. S. Ashok (Noroo) Dr. Eun-ee Seol Dr. C. Rathnasingh (GS Caltex) Dr. Mohan Raj (PRIST, India) Dr. Shengfang Zhou Ms. Yeoun-Joo Ko Mr. Mugesh S. Ms. Kelly Cheon Mr. Satish Ainala Ms. Christy Catherine (CNU) Mr. Suman Lama Mr. Thuan Phu Nguyen-Vo Ms. Trinh Nguyen Mr. Balaji Sekar Ms. Kyung-Mee Lee Mr. Yunxiao Liang Mr. Nguyen oai Nam Mr. Kwang-yun Jung Funding: Global Frontier Project: Advanced Biomass R&D Center (Grant No ); BK 21 Plus, Pusan National University

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