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Article(id=1308842076897378369, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308841897058198067, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2026-0246, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1772899200000, receivedDateStr=2026-03-08, revisedDate=1779292800000, revisedDateStr=2026-05-21, acceptedDate=null, acceptedDateStr=null, onlineDate=1789981868241, onlineDateStr=2026-09-21, pubDate=1783785600000, pubDateStr=2026-07-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1789981868241, onlineIssueDateStr=2026-09-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1789981868241, creator=13701087609, updateTime=1789981868241, updator=13701087609, issue=Issue{id=1308841897058198067, tenantId=1146029695717560320, journalId=1189982191388893191, year='2026', volume='61', issue='7', pageStart='2377', pageEnd='2820', issueExtLink='null', onlineDate='null', pubDate='1783785600000', pubDateStr='2026-07-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1789981825365, creator='13701087609', updateTime=1789984154811, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1308851667525792021, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308841897058198067, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1308851667525792022, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308841897058198067, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=2795, endPage=2800, ext={EN=ArticleExt(id=1308842077308420162, articleId=1308842076897378369, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Protein language model-guided enhancement of the catalytic activity of human arginase 1, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

Recombinant human arginase 1 (rhArg1) has significant therapeutic potential for the treatment of arginase 1 deficiency (ARG1-D) and arginine-auxotrophic cancers. However, its relatively low catalytic efficiency and limited in vivo stability restrict its clinical application. To enhance the catalytic performance of rhArg1, we employed the protein language model SaProt to perform zero-shot global mutational effect prediction across the entire rhArg1 sequence. Based on the predicted scores, the top 37 candidate variants were selected for experimental validation. Enzyme activity assays revealed that 16 of the 37 variants exhibited higher activity than the wild-type (WT) enzyme. Among them, the V30A, C45F, A56V, and H312P variants showed the most pronounced improvements, with catalytic activities increased by 33%, 23%, 22%, and 90%, respectively, compared with WT. Further kinetic characterization demonstrated that the H312P variant increased by 131% in catalytic efficiency (kcat/KM) relative to WT. These results indicate that the protein language model SaProt can effectively guide the rational engineering of arginase. The high-activity variants identified in this study provide promising candidate molecules for the treatment of ARG1-D and arginine-auxotrophic cancers.

, authors=Li-xia ZONG1, Ke-qing YAN1, Zhi-fei ZHANG1, Shuai FAN2, *, De-hong YU1, *, Zhao-yong YANG2, authorsList=Li-xia ZONG, Ke-qing YAN, Zhi-fei ZHANG, Shuai FAN, De-hong YU, Zhao-yong YANG, authorCompany=null, correspAuthors=Shuai FAN, De-hong YU, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2026 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1308842080298958923, articleId=1308842076897378369, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=蛋白质语言模型用于提高人精氨酸酶1的催化活性, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

重组人精氨酸酶1 (recombinant human arginase 1, rhArg1) 在治疗精氨酸酶1缺乏症(arginase 1 deficiency, ARG1-D) 及精氨酸营养缺陷型癌症中具有重要的潜在应用价值, 然而, 其相对较低的催化效率和有限的体内稳定性在一定程度上制约了其临床应用。为了提升rhArg1的催化性能, 本研究利用蛋白质语言模型SaProt对rhArg1进行零样本全局突变效应预测, 并根据预测分值筛选排名前37位的突变体进行实验验证。酶活性测定实验显示在37个突变体中, 共有16个突变体的酶活性高于野生型(wild type, WT)。其中, V30A、C45F、A56V和H312P这4个突变体的活性提升最为显著, 较WT分别提高33%、23%、22%和90%。进一步的酶动力学研究表明, 突变体H312P的催化效率(kcat/KM) 较WT提升了131%。上述结果表明, 蛋白质语言模型SaProt模型能够有效指导rhArg1的理性改造, 本研究获得的高活性突变体为ARG1-D治疗及精氨酸营养缺陷型肿瘤治疗提供了具有潜力的候选分子。

, authors=宗丽霞1, 严珂庆1, 张志斐1, 樊帅2, *, 于德红1, *, 杨兆勇2, authorsList=宗丽霞, 严珂庆, 张志斐, 樊帅, 于德红, 杨兆勇, authorCompany=null, correspAuthors=樊帅, 于德红, authorNote=

作者贡献:

宗丽霞、樊帅分析了实验数据, 撰写了论文; 宗丽霞、严珂庆完成了实验; 杨兆勇、张志斐、于德红负责设计本项实验; 全部作者均阅读并参与修改了本文。

, correspAuthorsNote=
樊帅, E-mail:
于德红, Tel: 86-315-8819004, E-mail:
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Nature, 2024, 630: 493-500., articleTitle=null, refAbstract=null)], funds=null, companyList=[AuthorCompany(id=1308842080487702604, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308842076897378369, xref=1, ext=[AuthorCompanyExt(id=1308842080496091213, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308842076897378369, companyId=1308842080487702604, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1School of Pharmacy, North China University of Science and Technology, Tangshan 063000, China), AuthorCompanyExt(id=1308842080504479822, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308842076897378369, companyId=1308842080487702604, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1华北理工大学药学院, 河北 唐山 063000)]), AuthorCompany(id=1308842080563200079, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308842076897378369, xref=2, ext=[AuthorCompanyExt(id=1308842080571588688, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308842076897378369, companyId=1308842080563200079, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1308842080579977297, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308842076897378369, companyId=1308842080563200079, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2中国医学科学院医药生物技术研究所, 北京 100050)])], figs=[ArticleFig(id=1308842084715561083, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308842076897378369, language=EN, label=null, caption=null, figureFileSmall=QvGXvsBD3fC3Rw/k0LiumA==, figureFileBig=VFqp0rbp450d2btXoo3QEw==, tableContent=null), ArticleFig(id=1308842084782669948, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308842076897378369, language=CN, label=Fig.1, caption= Predicted landscape of global mutational effects on rhArg1. A: Alanine; C: Cysteine; D: Aspartic acid; E: Glutamic acid; F: Phenylalanine; G: Glycine; H: Histidine; I: Isoleucine; K: Lysine; L: Leucine; M: Methionine; N: Asparagine; P: Proline; Q: Glutamine; R: Arginine; S: Serine; T: Threonine; V: Valine; W: Tryptophan; Y: Tyrosine, figureFileSmall=QvGXvsBD3fC3Rw/k0LiumA==, figureFileBig=VFqp0rbp450d2btXoo3QEw==, tableContent=null), ArticleFig(id=1308842085000773758, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308842076897378369, language=EN, label=null, caption=null, figureFileSmall=pWfpNwtVjP8jk6u+ghWJSQ==, figureFileBig=3oJrRtVmAlwWUsklRLds3g==, tableContent=null), ArticleFig(id=1308842085176934527, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308842076897378369, language=CN, label=Fig.2, caption= Visualization of mutation sites on the rhArg1 structure, figureFileSmall=pWfpNwtVjP8jk6u+ghWJSQ==, figureFileBig=3oJrRtVmAlwWUsklRLds3g==, tableContent=null), ArticleFig(id=1308842085256626304, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308842076897378369, language=EN, label=null, caption=null, figureFileSmall=QeA+c8LYwoiR8dhzoQxomg==, figureFileBig=2Z83K8vL2UEBzD4UgJzBBQ==, tableContent=null), ArticleFig(id=1308842085323735169, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308842076897378369, language=CN, label=Fig.3, caption= SDS-PAGE analysis of the purification process of WT and some of its mutant variants using Ni2+ columns. M: Page RulerTM protein ladder, figureFileSmall=QeA+c8LYwoiR8dhzoQxomg==, figureFileBig=2Z83K8vL2UEBzD4UgJzBBQ==, tableContent=null), ArticleFig(id=1308842085395038338, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308842076897378369, language=EN, label=null, caption=null, figureFileSmall=Hs6UA+e80ienp/OQI2RG3w==, figureFileBig=Q+gCuhTYYtOEnFOWHhb79A==, tableContent=null), ArticleFig(id=1308842085474730115, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308842076897378369, language=CN, label=Fig.4, caption= Enzyme activity of WT and mutant. n = 3, $ \overline{x} $ ± s. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.000 1 vs WT. ns: Not significant, figureFileSmall=Hs6UA+e80ienp/OQI2RG3w==, figureFileBig=Q+gCuhTYYtOEnFOWHhb79A==, tableContent=null), ArticleFig(id=1308842085533450372, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308842076897378369, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Primer namePrimer sequence (5′-3′)Primer namePrimer sequence (5′-3′)
E44G-FCTGAAAGAACAGGGATGTGATGTGK4L-FCATATGAGCGCACTAAGCCGTACC
E44G-RTCCCTGTTCTTTCAGTTTTTCCAGK4L-RTAGTGCGCTCATATGTATATCTCC
T127A-FGTTGATGCACATGCCGATATTAACK88S-FGTTGCAGAAGTTAGTAAGAACGGC
T127A-RGGCATGTGCATCAACCCAAATAACK88S-RACTAACTTCTGCAACTTTACCTGC
V30A-FGAAGGTCCTACCGCTCTGCGTAAAK88T-FGTTGCAGAAGTTACAAAGAACGGC
V30A-RAGCGGTAGGACCTTCTTCAACACCK88T-RTGTAACTTCTGCAACTTTACCTGC
C303A-FATTACCCTGGCAGCTTTTGGTCTGF240I-FCTGGATCCGAGCATTACCCCGGCA
C303A-RAGCTGCCAGGGTAATTGCAACTGCF240I-RAATGCTCGGATCCAGACCATCCAC
G82D-FGAACAGTTAGCAGATAAAGTTGCAC303G-FATTACCCTGGCAGGTTTTGGTCTG
G82D-RATCTGCTAACTGTTCGCTGGCTTTC303G-RACCTGCCAGGGTAATTGCAACTGC
G82E-FGAACAGTTAGCAGAAAAAGTTGCAE202D-FTTCAGCATGACCGATGTGGATCGC
G82E-RTTCTGCTAACTGTTCGCTGGCTTTE202D-RATCGGTCATGCTGAAGTACTTAAT
K88A-FGTTGCAGAAGTTGCAAAGAACGGCR222D-FTATCTGCTGGGTGATAAAAAACGT
K88A-RTGCAACTTCTGCAACTTTACCTGCR222D-RATCACCCAGCAGATAGCTCAGGGT
N90E-FGAAGTTAAAAAGGAAGGCCGCATTC45F-FAAAGAACAGGAATTTGATGTGAAG
N90E-RTTCCTTTTTAACTTCTGCAACTTTC45F-RAAATTCCTGTTCTTTCAGTTTTTC
H187K-FGATCCGGGTGAAAAATATATTCTGH312P-FCGTGAAGGTAATCCTAAACCGATT
H187K-RTTTTTCACCCGGATCCACATCGCGH312P-RAGGATTACCTTCACGTGCCAGACC
M276V-FGGTCTGGATATTGTGGAAGTTAATA307S-FTGTTTTGGTCTGTCACGTGAAGGT
M276V-RCACAATATCCAGACCGCTCAGCAGA307S-RTGACAGACCAAAACATGCCAGGGT
N90D-FGAAGTTAAAAAGGACGGCCGCATTT136P-FCCGCTGACCACCCCCAGCGGTAAT
N90D-RGTCCTTTTTAACTTCTGCAACTTTT136P-RGGGGGTGGTCAGCGGGGTGTTAAT
F240V-FCTGGATCCGAGCGTTACCCCGGCAP63D-FCCGAATGATAGCGATTTTCAGATT
F240V-RAACGCTCGGATCCAGACCATCCACP63D-RATCGCTATCATTCGGAATATCTGC
G82N-FGAACAGTTAGCAAATAAAGTTGCAI66N-FAGCCCGTTTCAGAATGTTAAAAAT
G82N-RATTTGCTAACTGTTCGCTGGCTTTI66N-RATTCTGAAACGGGCTATCATTCGG
G119A-FCATCCGGATCTGGCTGTTATTTGGP63N-FCCGAATGATAGCAATTTTCAGATT
G119A-RAGCCAGATCCGGATGAACACGTGCP63N-RATTGCTATCATTCGGAATATCTGC
A298D-FAATACCGCAGTTGATATTACCCTGC303S-FATTACCCTGGCATCTTTTGGTCTG
A298D-RATCAACTGCGGTATTAACGGTACGC303S-RAGATGCCAGGGTAATTGCAACTGC
T241A-FGATCCGAGCTTTGCCCCGGCAACCA307P-FTGTTTTGGTCTGCCACGTGAAGGT
T241A-RGGCAAAGCTCGGATCCAGACCATCA307P-RTGGCAGACCAAAACATGCCAGGGT
K88V-FGTTGCAGAAGTTGTAAAGAACGGCA56V-FGACCTGCCGTTTGTAGATATTCCG
K88V-RTACAACTTCTGCAACTTTACCTGCA56V-RTACAAACGGCAGGTCGCCGTAGTC
C45L-FAAAGAACAGGAACTTGATGTGAAGH187R-FGATCCGGGTGAACGTTATATTCTG
C45L-RAAGTTCCTGTTCTTTCAGTTTTTCH187R-RACGTTCACCCGGATCCACATCGCG
R222E-FTATCTGCTGGGTGAAAAAAAACGT
R222E-RTTCACCCAGCAGATAGCTCAGGGT
), ArticleFig(id=1308842085613142149, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308842076897378369, language=CN, label=Tab.1, caption=

Primers used in this study. Underline means mutation sites

, figureFileSmall=null, figureFileBig=null, tableContent=
Primer namePrimer sequence (5′-3′)Primer namePrimer sequence (5′-3′)
E44G-FCTGAAAGAACAGGGATGTGATGTGK4L-FCATATGAGCGCACTAAGCCGTACC
E44G-RTCCCTGTTCTTTCAGTTTTTCCAGK4L-RTAGTGCGCTCATATGTATATCTCC
T127A-FGTTGATGCACATGCCGATATTAACK88S-FGTTGCAGAAGTTAGTAAGAACGGC
T127A-RGGCATGTGCATCAACCCAAATAACK88S-RACTAACTTCTGCAACTTTACCTGC
V30A-FGAAGGTCCTACCGCTCTGCGTAAAK88T-FGTTGCAGAAGTTACAAAGAACGGC
V30A-RAGCGGTAGGACCTTCTTCAACACCK88T-RTGTAACTTCTGCAACTTTACCTGC
C303A-FATTACCCTGGCAGCTTTTGGTCTGF240I-FCTGGATCCGAGCATTACCCCGGCA
C303A-RAGCTGCCAGGGTAATTGCAACTGCF240I-RAATGCTCGGATCCAGACCATCCAC
G82D-FGAACAGTTAGCAGATAAAGTTGCAC303G-FATTACCCTGGCAGGTTTTGGTCTG
G82D-RATCTGCTAACTGTTCGCTGGCTTTC303G-RACCTGCCAGGGTAATTGCAACTGC
G82E-FGAACAGTTAGCAGAAAAAGTTGCAE202D-FTTCAGCATGACCGATGTGGATCGC
G82E-RTTCTGCTAACTGTTCGCTGGCTTTE202D-RATCGGTCATGCTGAAGTACTTAAT
K88A-FGTTGCAGAAGTTGCAAAGAACGGCR222D-FTATCTGCTGGGTGATAAAAAACGT
K88A-RTGCAACTTCTGCAACTTTACCTGCR222D-RATCACCCAGCAGATAGCTCAGGGT
N90E-FGAAGTTAAAAAGGAAGGCCGCATTC45F-FAAAGAACAGGAATTTGATGTGAAG
N90E-RTTCCTTTTTAACTTCTGCAACTTTC45F-RAAATTCCTGTTCTTTCAGTTTTTC
H187K-FGATCCGGGTGAAAAATATATTCTGH312P-FCGTGAAGGTAATCCTAAACCGATT
H187K-RTTTTTCACCCGGATCCACATCGCGH312P-RAGGATTACCTTCACGTGCCAGACC
M276V-FGGTCTGGATATTGTGGAAGTTAATA307S-FTGTTTTGGTCTGTCACGTGAAGGT
M276V-RCACAATATCCAGACCGCTCAGCAGA307S-RTGACAGACCAAAACATGCCAGGGT
N90D-FGAAGTTAAAAAGGACGGCCGCATTT136P-FCCGCTGACCACCCCCAGCGGTAAT
N90D-RGTCCTTTTTAACTTCTGCAACTTTT136P-RGGGGGTGGTCAGCGGGGTGTTAAT
F240V-FCTGGATCCGAGCGTTACCCCGGCAP63D-FCCGAATGATAGCGATTTTCAGATT
F240V-RAACGCTCGGATCCAGACCATCCACP63D-RATCGCTATCATTCGGAATATCTGC
G82N-FGAACAGTTAGCAAATAAAGTTGCAI66N-FAGCCCGTTTCAGAATGTTAAAAAT
G82N-RATTTGCTAACTGTTCGCTGGCTTTI66N-RATTCTGAAACGGGCTATCATTCGG
G119A-FCATCCGGATCTGGCTGTTATTTGGP63N-FCCGAATGATAGCAATTTTCAGATT
G119A-RAGCCAGATCCGGATGAACACGTGCP63N-RATTGCTATCATTCGGAATATCTGC
A298D-FAATACCGCAGTTGATATTACCCTGC303S-FATTACCCTGGCATCTTTTGGTCTG
A298D-RATCAACTGCGGTATTAACGGTACGC303S-RAGATGCCAGGGTAATTGCAACTGC
T241A-FGATCCGAGCTTTGCCCCGGCAACCA307P-FTGTTTTGGTCTGCCACGTGAAGGT
T241A-RGGCAAAGCTCGGATCCAGACCATCA307P-RTGGCAGACCAAAACATGCCAGGGT
K88V-FGTTGCAGAAGTTGTAAAGAACGGCA56V-FGACCTGCCGTTTGTAGATATTCCG
K88V-RTACAACTTCTGCAACTTTACCTGCA56V-RTACAAACGGCAGGTCGCCGTAGTC
C45L-FAAAGAACAGGAACTTGATGTGAAGH187R-FGATCCGGGTGAACGTTATATTCTG
C45L-RAAGTTCCTGTTCTTTCAGTTTTTCH187R-RACGTTCACCCGGATCCACATCGCG
R222E-FTATCTGCTGGGTGAAAAAAAACGT
R222E-RTTCACCCAGCAGATAGCTCAGGGT
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Enzymekcat/s-1KM /mmol·L-1kcat / KM /s-1·mmol-1·L
WT474.3 ± 10.0727.22 ± 2.217.42
V30A674.2 ± 16.6326.75 ± 2.0425.2
C45F611.7 ± 11.0926.71 ± 4.122.9
A56V606. ± 17.4728.59 ± 5.3621.2
H312P1 068. ± 23.5226.68 ± 3.7640.03
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Kinetic parameters of WT and its mutants. n = 3, $ \overline{x} $ ± s

, figureFileSmall=null, figureFileBig=null, tableContent=
Enzymekcat/s-1KM /mmol·L-1kcat / KM /s-1·mmol-1·L
WT474.3 ± 10.0727.22 ± 2.217.42
V30A674.2 ± 16.6326.75 ± 2.0425.2
C45F611.7 ± 11.0926.71 ± 4.122.9
A56V606. ± 17.4728.59 ± 5.3621.2
H312P1 068. ± 23.5226.68 ± 3.7640.03
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蛋白质语言模型用于提高人精氨酸酶1的催化活性
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宗丽霞 1 , 严珂庆 1 , 张志斐 1 , 樊帅 2, * , 于德红 1, * , 杨兆勇 2
药学学报 | 研究论文 2026,61(7): 2795-2800
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药学学报 |研究论文 2026 , 61 (7) : 2795 -2800
蛋白质语言模型用于提高人精氨酸酶1的催化活性
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宗丽霞1, 严珂庆1, 张志斐1, 樊帅2, * , 于德红1, * , 杨兆勇2
作者信息
  • 1华北理工大学药学院, 河北 唐山 063000
  • 2中国医学科学院医药生物技术研究所, 北京 100050
通讯作者:
樊帅, E-mail:
于德红, Tel: 86-315-8819004, E-mail:
作者简介:

作者贡献:

宗丽霞、樊帅分析了实验数据, 撰写了论文; 宗丽霞、严珂庆完成了实验; 杨兆勇、张志斐、于德红负责设计本项实验; 全部作者均阅读并参与修改了本文。

Protein language model-guided enhancement of the catalytic activity of human arginase 1
Li-xia ZONG1, Ke-qing YAN1, Zhi-fei ZHANG1, Shuai FAN2, * , De-hong YU1, * , Zhao-yong YANG2
Affiliations
  • 1School of Pharmacy, North China University of Science and Technology, Tangshan 063000, China
  • 2Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
出版时间: 2026-07-12 doi: 10.16438/j.0513-4870.2026-0246
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摘要
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重组人精氨酸酶1 (recombinant human arginase 1, rhArg1) 在治疗精氨酸酶1缺乏症(arginase 1 deficiency, ARG1-D) 及精氨酸营养缺陷型癌症中具有重要的潜在应用价值, 然而, 其相对较低的催化效率和有限的体内稳定性在一定程度上制约了其临床应用。为了提升rhArg1的催化性能, 本研究利用蛋白质语言模型SaProt对rhArg1进行零样本全局突变效应预测, 并根据预测分值筛选排名前37位的突变体进行实验验证。酶活性测定实验显示在37个突变体中, 共有16个突变体的酶活性高于野生型(wild type, WT)。其中, V30A、C45F、A56V和H312P这4个突变体的活性提升最为显著, 较WT分别提高33%、23%、22%和90%。进一步的酶动力学研究表明, 突变体H312P的催化效率(kcat/KM) 较WT提升了131%。上述结果表明, 蛋白质语言模型SaProt模型能够有效指导rhArg1的理性改造, 本研究获得的高活性突变体为ARG1-D治疗及精氨酸营养缺陷型肿瘤治疗提供了具有潜力的候选分子。

人精氨酸酶1  /  深度学习  /  蛋白质语言模型  /  酶动力学

Recombinant human arginase 1 (rhArg1) has significant therapeutic potential for the treatment of arginase 1 deficiency (ARG1-D) and arginine-auxotrophic cancers. However, its relatively low catalytic efficiency and limited in vivo stability restrict its clinical application. To enhance the catalytic performance of rhArg1, we employed the protein language model SaProt to perform zero-shot global mutational effect prediction across the entire rhArg1 sequence. Based on the predicted scores, the top 37 candidate variants were selected for experimental validation. Enzyme activity assays revealed that 16 of the 37 variants exhibited higher activity than the wild-type (WT) enzyme. Among them, the V30A, C45F, A56V, and H312P variants showed the most pronounced improvements, with catalytic activities increased by 33%, 23%, 22%, and 90%, respectively, compared with WT. Further kinetic characterization demonstrated that the H312P variant increased by 131% in catalytic efficiency (kcat/KM) relative to WT. These results indicate that the protein language model SaProt can effectively guide the rational engineering of arginase. The high-activity variants identified in this study provide promising candidate molecules for the treatment of ARG1-D and arginine-auxotrophic cancers.

human arginase 1  /  deep learning  /  protein language model  /  enzyme dynamics
宗丽霞, 严珂庆, 张志斐, 樊帅, 于德红, 杨兆勇. 蛋白质语言模型用于提高人精氨酸酶1的催化活性. 药学学报, 2026 , 61 (7) : 2795 -2800 . DOI: 10.16438/j.0513-4870.2026-0246
Li-xia ZONG, Ke-qing YAN, Zhi-fei ZHANG, Shuai FAN, De-hong YU, Zhao-yong YANG. Protein language model-guided enhancement of the catalytic activity of human arginase 1[J]. Acta Pharmaceutica Sinica, 2026 , 61 (7) : 2795 -2800 . DOI: 10.16438/j.0513-4870.2026-0246
正文
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精氨酸酶(arginase) 于1904年在脊椎动物的肝脏中被发现[1]。该酶主要分布于肝脏, 是肝脏尿素循环的六种关键酶之一, 参与机体对氨的解毒过程。它在尿素循环中的作用是催化L-精氨酸产生尿素和L-鸟氨酸, 对尿素类生物的氮排泄机制至关重要[2]。精氨酸酶有两个亚型: 精氨酸酶1 (arginase 1, Arg1) 和精氨酸酶2 (arginase 2, Arg2)。人类的Arg1基因在1980年被克隆出, 定位在6q23上[3]; Arg2基因于1996年被克隆出, 该基因定位到染色体14q24.1-24.3[4]。高分辨率晶体学表明, 两者都由3个相同的亚基组成, 是一种同源三聚体酶, 具有双核锰金属簇作为催化位点。Arg1的每个单体都表现出典型的罗斯曼折叠结构, 每个亚基的整体褶皱属于α/β家族, 由平行的8股β片组成, 两侧有许多α螺旋[5]。
发生在人类体内的Arg1基因碱基的突变、缺失、重复或插入导致酶功能部分或完全丧失的病症被称为精氨酸酶1缺乏症(arginase 1 deficiency, ARG1-D)[6, 7]。ARG1-D是一种常染色体隐性遗传疾病, 临床表现以进行性痉挛性截瘫为主, 超过一半的患者会出现癫痫发作。ARG1-D少有高氨血症的发作或程度较低, 这是与其他尿素循环障碍不同的地方[6, 8]。Aeglea BioTherapeutics研发的经聚乙二醇化的重组人精氨酸酶1 (recombinant human arginase 1, rhArg1) 已在欧盟和英国获得批准用于治疗2岁及以上患者的ARG1-D[8, 9]。但令人遗憾的是, 该药尚未在中国上市销售。另外, rhArg1也是一种重要的治疗用酶, 与超过30种严重疾病相关[10, 11], 涵盖心血管疾病、癌症及多种罕见代谢性疾病[12-17]。rhArg1被报道在血液系统恶性肿瘤(如急性白血病) 和实体肿瘤(如前列腺癌、黑色素瘤、乳腺癌等) 中都能有效地抑制肿瘤细胞生长和诱导其死亡[18], 并已作为针对精氨酸营养缺陷型肿瘤的潜在药物进入了临床试验阶段[19]。
尽管rhArg1具有较低免疫原性的优势, 但其对精氨酸的底物亲和力相对有限, 体内半衰期较短, 且最适催化条件与人体生理环境存在显著差异[17, 20]。上述因素共同限制了其在ARG1-D及肿瘤治疗中的体内催化效率和临床应用效果。因此, 有必要对rhArg1进行结构与功能优化, 以提升其体内稳定性和催化性能, 从而满足临床治疗需求。针对这一问题, 前人已积累了丰富的研究成果。Fernández等[21]通过理性设计hArg1及实验验证成功筛选出R21E突变体, 其催化效率较野生型提升13%; Madhagi等[22]通过计算机模拟设计hArg1发现G119L突变体是最稳定且活性最高的变体, 值得进一步实验验证。Fan等[23]采用半理性设计hArg1获得了29个突变体, 在2 mmol·L-1 Mn2+的条件下, N139K、Q143K、Q143S等单突变体的kcat相较于野生型提升了1.4~1.6倍, 双突变体T136D/Q143V的kcat则增加了1.5倍。
本研究旨在改造rhArg1, 以克服其在临床应用中的关键限制。为此, 我们利用深度学习模型SaProt[24]来捕捉突变对rhArg1功能的影响, 预测rhArg1序列适应度景观变化, 从而找到潜在的有益突变。此外还利用酶催化动力学和酶学性质分析对突变体进行评价, 为ARG1-D和癌症治疗提供新的候选分子。
材料与方法
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菌株与试剂   菌株E.coli BL21(DE3) (批号: WD0462843) 用于蛋白及其突变体的表达, 购自北京六合华大基因科技有限公司; 质粒pET-21a(+) 购自Novagen公司; 异丙基-β-D-硫代半乳糖苷(isopropyl-β-D-thiogalactoside, IPTG批号: 0487051951) 购自北京兰博利德商贸有限公司; 质粒提取试剂盒(批号: 25022) 购自北京康为世纪生物科技有限公司; PCR纯化试剂盒(批号: CJB061) 购自Genstar公司; Bradford蛋白浓度测定试剂盒(批号: 2025D0H) 购自上海碧云天生物技术有限公司; Dpn I限制性内切酶(批号: 7E0670D5) 购自南京Vazyme公司; KOD OneTM PCR Master Mix高保真酶(批号: 316600) 购自日本TOBOYO公司; Ni-NTA填料(批号: R30011410) 购自日本TaKaRa公司; 苯甲基磺酰氟(phenylmethanesulfonyl fluoride, PMSF, 批号: 2500010001) 购自北京索莱宝科技有限公司; 其余试剂均为国产分析纯。
rhArg1的理性设计    采用结构感知蛋白质语言模型SaProt (SaProt_650M_AF2)[24]对hArg1进行零样本突变效应预测。首先获取hArg1的三维结构(PDB: 2AEB, 结构缺失部分由AlphaFold3[25]进行补全), 随后按照SaProt模型要求, 将蛋白质结构编码为包含局部结构信息的序列表示。之后, 对hArg1全序列进行单点饱和突变扫描。对于每一个突变体, SaProt模型均基于当前序列-结构上下文, 计算突变氨基酸相对于野生型氨基酸的对数似然差值(log-likelihood difference), 根据计算所得数值对所有突变体进行排序。
rhArg1及其突变组合构建   rhArg1 (NCBI: P05089.2) 经密码子优化后由华大基因合成, 经酶切、连接得到表达质粒pET-21a-rhArg1, 以此为模板, 利用反向聚合酶链式反应(PCR) 引入突变, 突变引物如表1所示, 扩增反应体系为: 模板DNA 1 µL, ddH2O 21 µL, KOD OneTM PCR Master Mix 25 µL, 上下游引物各1.5 µL。PCR条件为: 98 ℃预变性2 min; 98 ℃变性10 s, 60 ℃退火15 s, 68 ℃延伸50 s, 30个循环; 最后68 ℃延伸5 min。得到的PCR产物经纯化后化转到E. coli BL21(DE3) 表达感受态中, 经测序验证后即得突变体表达菌株。
rhArg1及其突变体的表达与纯化   将rhArg1及突变体菌株按照2%的接种量接种于200 mL含有100 μg·mL-1氨苄青霉素的LB培养基中, 37 ℃、220 r·min-1振荡培养至OD600值为0.6~0.8, 加入终浓度为0.2 mmol·L-1的IPTG, 16 ℃、180 r·min-1低温诱导14~16 h后, 4 ℃、7 000 r·min-1, 离心4 min收集菌体, 用lysis buffer (50 mmol·L-1 NaH2PO4, 300 mmol·L-1 NaCl, 10 mmol·L-1咪唑pH 8.0) 重悬, 加入浓度为1 mmol·L-1的PMSF, 使用高压均质仪裂解菌体。4 ℃、11 000 r·min-1, 离心50 min后, 将用0.45 μm滤膜过滤的上清液与平衡好的Ni2+-NTA亲和层析柱4 ℃孵育1 h, 流穿液全部流出后使用5倍柱体积的washing buffer洗涤杂蛋白, 再用同样体积的elution buffer (50 mmol·L-1 NaH2PO4, 300 mmol·L-1 NaCl, 250 mmol·L-1咪唑, pH 8.0) 将目的蛋白洗脱。用30 kDa的超滤浓缩管浓缩目的蛋白并将缓冲液置换为20 mmol·L-1 Tris, 150 mmol·L-1 NaCl, pH 8.0。所有突变体均经十二烷基硫酸钠聚丙烯酰胺凝胶电泳(SDS-PAGE) 电泳分析其纯度及分子质量, 并使用Bradford蛋白浓度测定试剂盒测定其浓度。
rhArg1及其突变体酶活性测定   通过rhArg1及其突变体催化反应产物中的尿素来进行酶活性的定量检测。酶催化总反应体系为200 μL, 将0.7 µmol·L-1蛋白加入到含有50 mmol·L-1 L-精氨酸, 50 mmol·L-1 Tris-HCl (pH 7.4) 和0.2 mmol·L-1 Mn2+中37 ℃反应5 min, 加入30 µL含2-异亚硝基苯丙酮的酸混合物终止反应, 然后100 ℃反应45 min, 置于冰上冷却后12 000 r·min-1离心2 min, 在酶标仪下540 nm处测量吸光度, 并通过标准曲线确定生成尿素的量, 计算酶活并将每秒钟催化生成1 mmol尿素所需要的rhArg1量定义为1 U。
rhArg1及其突变体酶动力学测定   为评估酶的动力学参数KM和kcat, 以溶于50 mmol·L-1 Tris-HCl (pH 7.4), 0.2 mmol·L-1 Mn2+的2~100 mmol·L-1 L-精氨酸作为底物, 分别与适当稀释的酶液反应, 测定酶活性, 利用GraphPad Prism 8.0中Michaelis-Menten非线性拟合作图法计算KM和Vmax值, 并通过测定的蛋白浓度计算出对应的kcat。
统计学分析   统计学处理采用GraphPad Prism 8.0软件进行数据分析, 组间对比采用单因素方差分析。数据表示为平均值±标准差, P < 0.05为具有统计显著性。
结果与讨论
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1　基于蛋白质语言模型SaProt设计rhArg1
SaProt[24]是一种基于Transformer架构的结构感知蛋白质语言模型, 其利用大规模蛋白质序列与结构数据进行预训练, 通过联合学习蛋白质序列与局部结构信息, 实现对突变效应的泛化预测。本研究采用SaProt进行零样本预测, 将rhArg1的氨基酸序列输入模型, 计算各单点突变前后序列条件概率的变化, 以评估突变对蛋白功能稳定性的影响。在无需额外实验数据训练的前提下, 模型可直接输出各突变体相对于野生型的功能性预测分值。基于此, 我们构建了rhArg1的全局突变效应预测景观, 系统揭示全蛋白范围内不同残基替换对功能影响的强度及分布特征(图1)。
基于预测评分对全体单点突变进行排序分析发现, 大多数突变对酶催化活性表现为中性或负向影响, 仅少数突变显示潜在有益效应, 表明有益突变在整体突变空间中所占比例较低(图1)。根据预测分值筛选排名前37位的突变体用于后续活性验证。从rhArg1的三维结构分布来看, 这些候选突变位点分布较为分散, 主要位于蛋白表面区域, 而较少集中于催化核心区域(图2), 提示表面残基可能在调控酶活性或稳定性方面发挥潜在作用。
2　rhArg1及其突变体表达和酶活表征
rhArg1及其突变体质粒经大肠杆菌E.coli BL21(DE3) 异源表达, 高压均质仪破碎后获得可溶性蛋白, 高浓度咪唑可将通过His标签结合在Ni亲和层析柱上的蛋白洗脱下来, 经过浓缩、置换后得到较高纯度的蛋白, 目的蛋白的分子质量约为38 kDa, 全部蛋白的SDS-PAGE分析如图3所示, 蛋白大小与预期相符, 表明rhArg1及其突变体均实现了可溶性表达, 蛋白表达产量约为20 mg·L-1。
通过体外酶活性的定量检测, 结果显示在37个突变体中, 活性高于野生型(wild type, WT) 的突变体有16个, 其中突变体V30A、C45F、A56V、H312P、的活性相较于WT分别提高了33%、23%、22%和90%, 其余突变体的活性与WT相比未出现大幅提高, 因此在后续的实验中, 将不再对其进行研究。结果如图4所示。
3　rhArg1及其突变体的酶学性质研究
酶动力学实验结果见表2, 突变体V30A、C45F、A56V、H312P的kcat值相较于WT均有提高, 分别较WT提高了42%、28%、28%和125%。而在与底物的结合亲和力方面, 突变体V30A、C45F、H312P的KM值较WT略有降低, 说明这些突变体对以L-精氨酸为底物的结合能力在催化反应中得到提升, 表中其他突变体的KM值与WT相比有不同程度的增加, 表明这些突变体对底物的亲和能力有所减弱。表中所列突变体的kcat/KM值较WT均有不同程度提高, 尤其是H312P, 其催化效率是WT的2.3倍。
4　结论
蛋白语言模型SaProt经过大规模蛋白质序列数据集的训练, 能够适应多种蛋白质家族, 具有高效的微调能力和计算能力, 从而实现对突变效应的高效预测。该模型具有良好的泛化能力, 可适用于多种蛋白质家族的突变效应分析, 并在蛋白质理性设计中展现出较高的计算效率。与传统依赖大量实验筛选的方法相比, 基于蛋白质语言模型的设计策略能够显著降低蛋白质工程研究中的实验成本和时间消耗, 从而提高从头设计与定向改造蛋白质的效率。因此, SaProt模型为蛋白质工程优化及相关药物研发提供了一种具有潜力的重要计算工具。本研究利用SaProt模型对rhArg1进行零样本预测, 选取了37个突变体进行实验验证, 结果显示, 其中16个突变的活性得到了提升, 尤其是突变体V30A、C45F、A56V和H312P, 其活性相较于WT分别提高了33%、23%、22%和90%。突变体酶动力学实验显示, 突变体V30A、C45F、A56V和H312P的kcat值分别较WT提高了42%、28%、28%和125%, 表明这些突变体每秒钟转换底物的分子数增多。相较于WT, H312P的kcat/KM值提高了131%, 说明该突变体在底物结合与催化转化效率方面均得到优化, 从而显著提升了L-精氨酸向产物转化的整体催化效率。上述结果表明, 基于SaProt模型筛选获得的突变体在催化性能方面具有明显优势, 为进一步开展rhArg1的理性改造与功能优化提供了重要依据。

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doi: 10.16438/j.0513-4870.2026-0246
  • 接收时间：2026-03-08
  • 首发时间：2026-09-21
  • 出版时间：2026-07-12
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  • 收稿日期：2026-03-08
  • 修回日期：2026-05-21
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    1华北理工大学药学院, 河北 唐山 063000
    2中国医学科学院医药生物技术研究所, 北京 100050

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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
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