神经酰胺类鞘脂的绿色生物制造

doi:10.12211/2096-8280.2024-059

摘要/Abstract

摘要：

神经酰胺是一种存在于所有真核生物中的多功能生物活性物质，在细胞信号转导、细胞增殖、分化、凋亡和免疫调节中发挥着重要作用。神经酰胺天然存在于皮肤角质层中，起着支持肌肤屏障、保持水分、抗氧化衰老、抗菌抗炎等作用。因此，神经酰胺及其衍生物在化妆品、生物医药、功能食品等领域具有广阔的市场前景。神经酰胺构型存在多个立体中心，化学从头合成难度大，已知市售的天然或类神经酰胺化合物主要是通过传统天然提取法及生物化学相结合的半合成法获得。近年来，利用微生物合成神经酰胺等鞘脂类化合物已有报道，但从头合成效率还处于较低水平，如何实现细胞工厂高效生产神经酰胺具有重大意义。本文首先从神经酰胺的生理功能和应用出发，系统地综述了神经酰胺类物质的生理效应及功能；其次阐述了神经酰胺的天然提取方法、神经酰胺及其前体化合物的化学合成方法；接下来，从鞘脂合成途径及关键酶出发介绍，引出途径调控与优化、产物的运输储存与分泌、关键酶的挖掘与表达等改造策略；最后，从神经酰胺合成面临的聚集毒性、高效运输分泌、数字化改造催化元件、基因调控靶点的拓展等方面进行了展望。合成生物学和生物技术的持续进步有助于扩大微生物细胞工厂的生产能力，实现神经酰胺等鞘脂类化合物的可持续绿色生物制造。

关键词: 神经酰胺, 微生物细胞工厂, 生物合成, 鞘脂, 鞘氨醇碱

Abstract:

Ceramide, a fundamental bioactive molecule found ubiquitously in eukaryotic organisms, exerts profound regulatory effects on cellular physiology, encompassing critical roles in signaling cascades, cellular proliferation, differentiation, apoptosis, and immunomodulation. In dermatology, ceramides play an indispensable role as constituents of the stratum corneum, the outermost layer of the skin, where they are crucial for maintaining the integrity of the epidermal barrier, regulating moisture retention, combating oxidative stress linked to aging, and exhibiting notable antimicrobial and anti-inflammatory properties. The multifaceted biological functions of ceramides underscore their extensive applications across various industries, including cosmetics, biomedicine, functional food, and animal nutrition, highlighting their significant market potential and therapeutic value. The chemical synthesis of ceramides poses substantial challenges due to the intricate stereochemistry involved, necessitating precise control over synthetic pathways. As a result, current commercial sources predominantly rely on semi-synthetic methods that integrate traditional natural extraction techniques with biochemical transformations of sphingolipid precursors to achieve targeted ceramide structures. Recent advancements have explored microbial systems for the production of sphingolipids, including ceramides, offering promising avenues for scalable and sustainable synthesis. However, optimizing de novo synthesis efficiency in microbial cell factories remains a primary research focus. Strategies aimed at enhancing ceramide yield and purity through metabolic engineering and pathway optimization are pivotal for advancing industrial applications. This paper provides a systematic review of the physiological effects and functions of ceramides, encompassing their physiological roles and various applications. It begins with an overview of ceramide extraction methods, including both natural extraction techniques and chemical synthesis approaches for ceramides and their precursor compounds. Subsequently, the review addresses the sphingolipid synthesis pathway and its associated key enzymes, detailing strategies for pathway regulation and optimization, as well as aspects of product transport, storage, and secretion. Additionally, it explores the identification and expression of key enzyme. The paper concludes by examining future directions in the field, such as addressing aggregation toxicity in ceramide synthesis, enhancing transport and secretion mechanisms, advancing digital modifications of catalytic elements, and expanding gene regulatory target exploration. By synthesizing current knowledge and highlighting avenues for innovation, this review aims to catalyze further research efforts toward achieving efficient ceramide production. Ultimately, optimizing ceramide synthesis has the potential to unlock its full potential across diverse sectors, contributing to advancements in skincare, therapeutics, and functional materials. The integration of microbial systems is particularly promising for expanding production capabilities while addressing sustainability concerns in ceramide manufacturing. Continued advancements in synthetic biology and biotechnology are expected to revolutionize the landscape of ceramide applications, paving the way for enhanced therapeutic interventions and novel industrial applications in the years ahead.

Key words: ceramide, microbial cell factories, biosynthesis, sphingolipids, sphingosine alkali

中图分类号:

Q819

鲁锦畅, 武耀康, 吕雪芹, 刘龙, 陈坚, 刘延峰. 神经酰胺类鞘脂的绿色生物制造[J]. 合成生物学, DOI: 10.12211/2096-8280.2024-059.

Jinchang LU, Yaokang WU, Xueqin LV, Long LIU, Jian CHEN, Yanfeng LIU. Green biomanufacturing of ceramide sphingolipids[J]. Synthetic Biology Journal, DOI: 10.12211/2096-8280.2024-059.

图/表 10

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91	REN J, SAIED E M, ZHONG A, et al. Tsc3 regulates SPT amino acid choice in Saccharomyces cerevisiae by promoting alanine in the sphingolipid pathway[J]. Journal of Lipid Research, 2018, 59(1): 2126–2139.
92	SCHÄFER J H, KÖRNER C, ESCH B M, et al. Structure of the ceramide-bound SPOTS complex [J]. Nature Communications, 2023, 14(1): 6196.
93	BEELER T, BACIKOVA D, GABLE K, et al. The Saccharomyces cerevisiae TSC10/YBR265w Gene Encoding 3-Ketosphinganine Reductase Is Identified in a Screen for Temperature-sensitive Suppressors of the Ca2+-sensitive csg2Δ Mutant*[J]. Journal of Biological Chemistry, 1998, 273(46): 30688-30694.
94	BRESLOW D K, COLLINS S R, BODENMILLER B, et al. Orm family proteins mediate sphingolipid homeostasis[J]. Nature, 2010, 463(7284): 1048-1053.
95	LIU Q, CHAN A K N, CHANG W H, et al. 3-Ketodihydrosphingosine reductase maintains ER homeostasis and unfolded protein response in leukemia[J]. Leukemia, 2022, 36(1): 100-110.
96	ZHAO P, ZHUANG Z, GUAN X, et al. Crystal structure of the 3-ketodihydrosphingosine reductase TSC10 from Cryptococcus neoformans [J]. Biochemical and Biophysical Research Communications, 2023, 670: 73-78.
97	SCHORLING S, VALLÉE B, BARZ W P, et al. Lag1p and Lac1p Are Essential for the Acyl-CoA–dependent Ceramide Synthase Reaction in Saccharomyces cerevisae [J]. Molecular Biology of the Cell, 2001, 12(11): 3417-3427.
98	GUILLAS I, KIRCHMAN P A, CHUARD R, et al. C26‐CoA‐dependent ceramide synthesis of Saccharomyces cerevisiae is operated by Lag1p and Lac1p[J]. The EMBO Journal, 2001, 20(11): 2655-2665.
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	出发底物	产物	总收率	参考文献
鞘氨醇碱从头合成	2-叠氮-4-硝基苯基磺酸衍生物	鞘氨醇；植物鞘氨醇	58%	^[48]
	立体选择性的环氧化物	鞘氨醇	51%	^[49]
	D-葡萄糖衍生物	D-赤式鞘氨醇；D-苏式鞘氨醇	52%	^[35]
	L-丝氨酸	鞘氨醇；鞘磷脂；1-磷酸鞘氨醇；鞘氨醇衍生物	37%	^[34]
	N-Boc-L-丝氨酸	鞘氨醇	71%	^[33]
神经酰胺从头合成	三羟甲基氨基甲烷；脂肪酸羟基取代物	神经酰胺类似物	33%~65%	^[42]
	（2S）-2-氨基苯乙醇（苯甘氨醇）；（1R,2R）2-氨基-1-苯基-1,3-丙二醇；（S）-2-氨基（-4-甲氧基）苯乙醇	神经酰胺类似物	63.5%	^[50]
	羟化脂肪酸；环氧甘油基醚	神经酰胺类似物	60%~75%	^[51]
	N-十六烷基-2-氨基乙醇；环己烷；丙二酸二甲酯	神经酰胺类似物	69%	^[52]
	C16-烷基烯二聚体；二乙醇胺/N-甲基-2,3,4,5,6无羟基己胺/D-氨基葡萄糖/3-氨基-1,2-丙二醇/N-（1,3二羟基异丙基）胺/ N-（2,3,4,5,6-五羟基己基）胺等	神经酰胺类似物	20%~90%	^[53-54]
脂肪酸与鞘碱化学法合成神经酰胺	神经鞘氨醇；不同碳链长度有机酸	神经酰胺类似物	51%~96%	^[21]
	共轭羧酸与N‑羟基琥珀酰亚胺；鞘氨醇	含共轭羧酸的神经酰胺	50%~70%	^[43]
	羧酸；植物鞘氨醇	神经酰胺III	84％	^[55]
脂肪酸与鞘碱生物酶法法合成神经酰胺	二氢鞘氨醇；脂肪酸 Novozym 435	神经酰胺NG	70%~98%	^[46]
	活化的羧酸衍生物；植物鞘氨醇/二氢鞘氨醇；Novozym 435	神经酰胺	98%~99.7%	^[47]
	植物鞘氨酸；脂肪酸；Novozym 435	神经酰胺III	94%	^[44]

	出发底物	产物	总收率	参考文献
鞘氨醇碱从头合成	2-叠氮-4-硝基苯基磺酸衍生物	鞘氨醇；植物鞘氨醇	58%	^[48]
	立体选择性的环氧化物	鞘氨醇	51%	^[49]
	D-葡萄糖衍生物	D-赤式鞘氨醇；D-苏式鞘氨醇	52%	^[35]
	L-丝氨酸	鞘氨醇；鞘磷脂；1-磷酸鞘氨醇；鞘氨醇衍生物	37%	^[34]
	N-Boc-L-丝氨酸	鞘氨醇	71%	^[33]
神经酰胺从头合成	三羟甲基氨基甲烷；脂肪酸羟基取代物	神经酰胺类似物	33%~65%	^[42]
	（2S）-2-氨基苯乙醇（苯甘氨醇）；（1R,2R）2-氨基-1-苯基-1,3-丙二醇；（S）-2-氨基（-4-甲氧基）苯乙醇	神经酰胺类似物	63.5%	^[50]
	羟化脂肪酸；环氧甘油基醚	神经酰胺类似物	60%~75%	^[51]
	N-十六烷基-2-氨基乙醇；环己烷；丙二酸二甲酯	神经酰胺类似物	69%	^[52]
	C16-烷基烯二聚体；二乙醇胺/N-甲基-2,3,4,5,6无羟基己胺/D-氨基葡萄糖/3-氨基-1,2-丙二醇/N-（1,3二羟基异丙基）胺/ N-（2,3,4,5,6-五羟基己基）胺等	神经酰胺类似物	20%~90%	^[53-54]
脂肪酸与鞘碱化学法合成神经酰胺	神经鞘氨醇；不同碳链长度有机酸	神经酰胺类似物	51%~96%	^[21]
	共轭羧酸与N‑羟基琥珀酰亚胺；鞘氨醇	含共轭羧酸的神经酰胺	50%~70%	^[43]
	羧酸；植物鞘氨醇	神经酰胺III	84％	^[55]
脂肪酸与鞘碱生物酶法法合成神经酰胺	二氢鞘氨醇；脂肪酸 Novozym 435	神经酰胺NG	70%~98%	^[46]
	活化的羧酸衍生物；植物鞘氨醇/二氢鞘氨醇；Novozym 435	神经酰胺	98%~99.7%	^[47]
	植物鞘氨酸；脂肪酸；Novozym 435	神经酰胺III	94%	^[44]

宿主	产物	底物碳源	策略	产量	参考文献
威克汉姆西弗酵母	三乙酰鞘氨醇	葡萄糖	异源表达棉桃阿舒来源laf1和des1；突变SYR、DES	33.45 mg/g DCW（500 mL挡板摇瓶）	^[61]
威克汉姆西弗酵母（P.ciferrii lig4D strain CS.PCDPro2）	四乙酰植物鞘氨醇	33 g/L葡萄糖	阻断shm1、shm2；缺失cha1；删除lcb4；过表达lcb1、lcb2；敲除orm1、orm2；过表达sur2	199 mg/g DCW；2 g/L （摇瓶培养）	^[68]
威克汉姆西弗酵母（NRRL Y1031）	四乙酰植物鞘氨醇	33 g/L葡萄糖	-	291.2±63.7 mg/L （120 mL/500 mL挡板摇瓶）	^[69]
威克汉姆西弗酵母 NRRL Y-1031（M40）	四乙酰植物鞘氨醇	30 g/L葡萄糖 30g /L糖蜜	EMS诱变；BODIPY 505/515染色；荧光激活细胞分选（FACS）	2.895 g/L （5.6 L生物反应器）	^[70]
酿酒酵母K26	二乙酰植物鞘氨醇	33 g/L葡萄糖	质粒表达异源基因sli1、atf2	4.3±0.8 mg/L （120 mL/500 mL挡板摇瓶）	^[69]
酿酒酵母K26	三乙酰植物鞘氨醇	33 g/L葡萄糖	质粒表达异源基因sli1、atf2	1.2±0.1 mg/L （120 mL/500 mL挡板摇瓶）	^[69]
解脂耶氏酵母PO1g（MatA, leu2-270, ura3-302::URA3, xpr2-332. axp-2）	四乙酰植物鞘氨醇	200 g/L甘油橄榄油	异源表达sli1、atf2；删除lcb4基因；有性杂交；发酵优化	650±24 mg/L （5 L生物反应器）	^[57]
威克汉姆西弗酵母 F-60-10A NRRL1031 诱变后菌株：Mutant736	四乙酰植物鞘氨醇	5 g/L丝氨酸；50 g/L甘油；补加甘油	γ射线诱变	17.7 g/L （3 L生物反应器）	^[71]
威克汉姆西弗酵母	四乙酰植物鞘氨醇	50 g/L甘油；5 g/L L‑丝氨酸	ARTP诱变	30.47 g/L （5 L生物反应器）	^[72]
威克汉姆西弗酵母 DSCC 7-25（KCCM-10131）	四乙酰植物鞘氨醇	25~35 g/L甘油	从NRRL Y-1031单倍体分离	14 g/L （500 L生物反应器）	^[73]
威克汉姆西弗酵母CGMCC19562	四乙酰植物鞘氨醇	6.0 g/L L‑丝氨酸；，42.0 g/L甘油	单倍体分离	22.14 g/L （生物反应器）	^[74]
酿酒酵母 CEN.PK2‑1D	植物鞘氨醇	500 g/L葡萄糖	敲除lcb4、shm2、cha1；orm2:: tsc10；elo3::sur2；shm1::lcb1,lcb2； delta 22::hac1	2817 mg/L；150.54 mg/g干重（5 L生物反应器）	^[75]
酿酒酵母NCYC 3608（MATalpha gal2 ho::HygMX ura3::KanMX）	植物鞘氨醇	20 g/L葡萄糖	缺失his3、leu2、ura3、cha1、cha2、lcb4、lcb5、orm2；质粒过表达ARS/CEN/URA/ScTSC10/ScSUR2、ARS/CEN/HIS/ScLCB1/ScLCB2、ARS/CEN/LEU	2169 mg/L	^[76]
酿酒酵母KCCM50515	神经酰胺	20 g/L葡萄糖	发酵优化	1.46 mg/L	^[56]
酿酒酵母 KCCM 50515（Matα ura3-52 lys2-801 ade2-101 trp1-∆63 his3-∆200 leu2-∆1）	神经酰胺	20 g/L葡萄糖	过表达tscl0	9.8 mg/g cell	^[77]
酿酒酵母	神经酰胺	葡萄糖；半乳糖	过表达tsc10	10.52 mg/g cell	^[78]
酿酒酵母 SCEL2,1	神经酰胺	葡萄糖；半乳糖	过表达lcb1、lcb2	10.08 mg /g cell	^[78]
酿酒酵母 SCEG1C1	神经酰胺	葡萄糖；半乳糖	过表达lag1、lac1	9.88 mg/g cell	^[78]
酿酒酵母	神经酰胺NS	葡萄糖	敲除sur2和scs7；引入人类鞘脂去饱和酶基因des1；失活ydc1；过表达isc1；des1基因产物的内质网定位	未定量	^[79]
巴斯德毕赤酵母GS115	神经酰胺（d18:0）	10 g/L甘油	敲除Ku70 同源的基因 PAS_chr3_0329；敲除orm1、orm2 同系物同源基因 PAS_chr4_0427	90.22 mg/L	^[58]

宿主	产物	底物碳源	策略	产量	参考文献
威克汉姆西弗酵母	三乙酰鞘氨醇	葡萄糖	异源表达棉桃阿舒来源laf1和des1；突变SYR、DES	33.45 mg/g DCW（500 mL挡板摇瓶）	^[61]
威克汉姆西弗酵母（P.ciferrii lig4D strain CS.PCDPro2）	四乙酰植物鞘氨醇	33 g/L葡萄糖	阻断shm1、shm2；缺失cha1；删除lcb4；过表达lcb1、lcb2；敲除orm1、orm2；过表达sur2	199 mg/g DCW；2 g/L （摇瓶培养）	^[68]
威克汉姆西弗酵母（NRRL Y1031）	四乙酰植物鞘氨醇	33 g/L葡萄糖	-	291.2±63.7 mg/L （120 mL/500 mL挡板摇瓶）	^[69]
威克汉姆西弗酵母 NRRL Y-1031（M40）	四乙酰植物鞘氨醇	30 g/L葡萄糖 30g /L糖蜜	EMS诱变；BODIPY 505/515染色；荧光激活细胞分选（FACS）	2.895 g/L （5.6 L生物反应器）	^[70]
酿酒酵母K26	二乙酰植物鞘氨醇	33 g/L葡萄糖	质粒表达异源基因sli1、atf2	4.3±0.8 mg/L （120 mL/500 mL挡板摇瓶）	^[69]
酿酒酵母K26	三乙酰植物鞘氨醇	33 g/L葡萄糖	质粒表达异源基因sli1、atf2	1.2±0.1 mg/L （120 mL/500 mL挡板摇瓶）	^[69]
解脂耶氏酵母PO1g（MatA, leu2-270, ura3-302::URA3, xpr2-332. axp-2）	四乙酰植物鞘氨醇	200 g/L甘油橄榄油	异源表达sli1、atf2；删除lcb4基因；有性杂交；发酵优化	650±24 mg/L （5 L生物反应器）	^[57]
威克汉姆西弗酵母 F-60-10A NRRL1031 诱变后菌株：Mutant736	四乙酰植物鞘氨醇	5 g/L丝氨酸；50 g/L甘油；补加甘油	γ射线诱变	17.7 g/L （3 L生物反应器）	^[71]
威克汉姆西弗酵母	四乙酰植物鞘氨醇	50 g/L甘油；5 g/L L‑丝氨酸	ARTP诱变	30.47 g/L （5 L生物反应器）	^[72]
威克汉姆西弗酵母 DSCC 7-25（KCCM-10131）	四乙酰植物鞘氨醇	25~35 g/L甘油	从NRRL Y-1031单倍体分离	14 g/L （500 L生物反应器）	^[73]
威克汉姆西弗酵母CGMCC19562	四乙酰植物鞘氨醇	6.0 g/L L‑丝氨酸；，42.0 g/L甘油	单倍体分离	22.14 g/L （生物反应器）	^[74]
酿酒酵母 CEN.PK2‑1D	植物鞘氨醇	500 g/L葡萄糖	敲除lcb4、shm2、cha1；orm2:: tsc10；elo3::sur2；shm1::lcb1,lcb2； delta 22::hac1	2817 mg/L；150.54 mg/g干重（5 L生物反应器）	^[75]
酿酒酵母NCYC 3608（MATalpha gal2 ho::HygMX ura3::KanMX）	植物鞘氨醇	20 g/L葡萄糖	缺失his3、leu2、ura3、cha1、cha2、lcb4、lcb5、orm2；质粒过表达ARS/CEN/URA/ScTSC10/ScSUR2、ARS/CEN/HIS/ScLCB1/ScLCB2、ARS/CEN/LEU	2169 mg/L	^[76]
酿酒酵母KCCM50515	神经酰胺	20 g/L葡萄糖	发酵优化	1.46 mg/L	^[56]
酿酒酵母 KCCM 50515（Matα ura3-52 lys2-801 ade2-101 trp1-∆63 his3-∆200 leu2-∆1）	神经酰胺	20 g/L葡萄糖	过表达tscl0	9.8 mg/g cell	^[77]
酿酒酵母	神经酰胺	葡萄糖；半乳糖	过表达tsc10	10.52 mg/g cell	^[78]
酿酒酵母 SCEL2,1	神经酰胺	葡萄糖；半乳糖	过表达lcb1、lcb2	10.08 mg /g cell	^[78]
酿酒酵母 SCEG1C1	神经酰胺	葡萄糖；半乳糖	过表达lag1、lac1	9.88 mg/g cell	^[78]
酿酒酵母	神经酰胺NS	葡萄糖	敲除sur2和scs7；引入人类鞘脂去饱和酶基因des1；失活ydc1；过表达isc1；des1基因产物的内质网定位	未定量	^[79]
巴斯德毕赤酵母GS115	神经酰胺（d18:0）	10 g/L甘油	敲除Ku70 同源的基因 PAS_chr3_0329；敲除orm1、orm2 同系物同源基因 PAS_chr4_0427	90.22 mg/L	^[58]

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