更新于：2024-05-01

PCBD1

pterin-4 alpha-carbinolamine dehydratase 1

更新于：2024-05-01

基本信息

别名

4-alpha-hydroxy-tetrahydropterin dehydratase、DCOH、Dimerization cofactor of hepatocyte nuclear factor 1-alpha

+ [9]

简介

Involved in tetrahydrobiopterin biosynthesis (By similarity). Seems to both prevent the formation of 7-pterins and accelerate the formation of quinonoid-BH2. Coactivator for HNF1A-dependent transcription (By similarity). Regulates the dimerization of homeodomain protein HNF1A and enhances its transcriptional activity (By similarity). Also acts as a coactivator for HNF1B-dependent transcription (PubMed:24204001).

关联

100 项与 PCBD1 相关的临床结果

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100 项与 PCBD1 相关的转化医学

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0 项与 PCBD1 相关的专利（医药）

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162

项与 PCBD1 相关的文献（医药）

2024-01-13·Journal of bioscience and bioengineering

Development of a novel tyrosine-based selection system for generation of recombinant Chinese hamster ovary cells

Article

作者: Cheng, Jun ; Zhang, Yanmin ; Tian, Yuan ; Cao, Lei ; Liu, Xuping ; Miao, Shiwei ; Zhao, Liang ; Ye, Qian ; Zhou, Yan ; Tan, Wen-Song

Efficiently expanding Chinese hamster ovary (CHO) cells, which serve as the primary host cells for recombinant protein production, have gained increasing industrial significance. A significant hurdle in stable cell line development is the low efficiency of the target gene integrated into the host genome, implying the necessity for an effective screening and selection procedure to separate these stable cells. In this study, the genes of phenylalanine hydroxylase (PAH) and pterin 4 alpha carbinolamine dehydratase 1 (PCBD1), which are key enzymes in the tyrosine synthesis pathway, were utilized as selection markers and transduced into host cells together with the target genes. This research investigated the enrichment effect of this system and advanced further in understanding its benefits for cell line development and rCHO cell culture. A novel tyrosine-based selection system that only used PCBD1 as a selection marker was designed to promote the enrichment effect. Post 9 days of starvation, positive transductants in the cell pool approached 100%. Applied the novel tyrosine-based selection system, rCHO cells expressing E2 protein were generated and named CHO TS cells. It could continue to grow, and the yield of E2 achieved 95.95 mg/L in a tyrosine-free and chemically-defined (CD) medium. Herein, we introduced an alternative to antibiotic-based selections for the establishment of CHO cell lines and provided useful insights for the design and development of CD medium.

2023-10-11·Molecular genetics & genomic medicine

Genotypic variants of the tetrahydrobiopterin (BH4) biosynthesis genes in patients with hyperphenylalaninemia from different regions of Iran.

Article

作者: Seyed Reza Kazemi Nezhad ; Pegah Namdar Aligoodarzi ; Golale Rostami ; Gholamreza Shariati ; Hamid Galehdari ; Alihossein Saberi ; Alireza Sedaghat ; Mohammad Hamid

BACKGROUND:

Hyperphenylalaninemia (HPA) is a metabolic disorder classified into phenylalanine-4-hydroxylase (PAH) and non-PAH deficiency. The latter is produced by mutations in genes involved in the tetrahydrobiopterin (BH4) biosynthesis pathway and DNAJC12 pathogenetic variants. The BH4 metabolism, including de novo biosynthesis involved genes (i.e., guanosine 5'-triphosphate cyclohydrolase I (GTPCH/GCH1), sepiapterin reductase (SR/SPR), 6-pyruvoyl-tetrahydropterin synthase (PTPS/PTS)), and two genes that play roles in cofactor regeneration pathway (i.e., dihydropteridine reductase (DHPR/QDPR) and pterin-4α-carbinolamine dehydratase (PCD/PCBD1)). The subsequent systemic hyperphenylalaninemia and monoamine neurotransmitter deficiency lead to neurological consequences. The high rate of consanguineous marriages in Iran substantially increases the incidence of BH4 deficiency.

METHODS:

We utilized the Sanger sequencing technique in this study to investigate 14 Iranian patients with non-PAH deficiency. All affected subjects in this study had HPA and no mutation was detected in their PAH gene.

RESULTS:

We successfully identified six mutant alleles in BH4-deficiency-associated genes, including three novel mutations: one in QDPR, one in PTS, and one in the PCBD1 gene, thus giving a definite diagnosis to these patients.

CONCLUSION:

In this light, appropriate patient management may follow. The clinical effect of reported variants is essential for genetic counseling and prenatal diagnosis in the patients' families and significant for the improvement of precision medicine.

2023-08-17·Journal of personalized medicine

Comprehensive Molecular Evaluation of HNF-1 Alpha, miR-27a, and miR-146 Gene Variants and Their Link with Predisposition and Progression in Type 2 Diabetes Patients.

Article

作者: Rashid Mir ; Imadeldin Elfaki ; M E Elangeeb ; Mamdoh S Moawadh ; Faris Jamal Tayeb ; Jameel Barnawi ; Ibrahim Altedlawi Albalawi ; Amnah A Alharbi ; Marwan H Alhelali ; Basim S O Alsaedi

BACKGROUND:

Type 2 diabetes (T2D) is a metabolic condition induced by insulin resistance and pancreatic beta cell dysfunction. MicroRNAs (miRNAs) have biological significance because they regulate processes such as the molecular signaling pathways involved in the pathophysiology of diabetes mellitus. The hepatocyte nuclear factor-1 alpha (HNF-1 alpha) is a transcription factor found in hepatocytes and the pancreas. Mutations in the HNF-1 alpha gene were reportedly associated with maturity-onset diabetes of the young (MODY). The objective of the present study was to examine the associations between MiR-27a, MiR-146, and HNF-1 alpha single-nucleotide variations (SNVs) with T2D risk in the Saudi population.

METHODOLOGY:

We evaluated the association of SNVs of miR-27a rs895819 A>G, 146a-rs2910164 C>G, and HNF-1 alpha rs1169288 G>T (I27L) with the risk of T2D in Saudi patients with the Amplification Refractory Mutation System PCR (ARMS-PCR). For the miR-27a SNVs, we used 115 cases (82 males, 33 females) and 117 matched healthy controls (HCs); for the Mir-146 SNVs, we used 103 cases (70 males, 33 females) and 108 matched HCs; and for the HNF-1 alpha, we employed 110 patients (80 males, 30 females) and 110 HCs. The blood biochemistry of the participants was essayed using commercial kits, and the methods of statistical analysis used were the Chi-square test, the Fisher exact test, and a multivariate analysis based on logistic regression, like the odds ratio (OD) and risk ratio (RR), with 95% confidence intervals (CIs).

RESULTS:

The MiR-27a rs895819 AG genotype was linked to increased T2D susceptibility, with OR = 2.01 and p-value = 0.011, and the miR-146 rs2910164 CG genotype and C allele were linked to an elevated risk of T2D, with OR = 2.75, p-value < 0.0016, OR = 1.77, and p-value = 0.004. The results also showed that the GT genotype and T allele of the HNF-1 alpha (rs1169288) G>T is linked to T2D, with OR = 2.18, p-value = 0.0061, and 1.77, p-value = 0.0059.

CONCLUSIONS:

The SNVs in miR-27a, miR-146, and HNF-1 alpha can be potential loci for T2D risk. The limitations of this study include the relatively small sample size and the fact that it was a cross-sectional study. To our knowledge, this is the first study to highlight the association between miR-27a, miR-146, and HNF-1 alpha SNVs and the risk of T2D in the Saudi population. Future large-scale case-control studies, as well as studies on the functions of the proteins and protein interaction studies for HNF-1 alpha, are required to verify our findings. Furthermore, these findings can be used for the identification and stratification of at-risk populations via genetic testing for T2D-prevention strategies.

项与 PCBD1 相关的新闻（医药）

2023-01-22

·MedCity News

Nvidia’s AI Tech Designs Proteins Never Seen in Nature, Pointing Way to New Therapies

Engineering techniques are already used to design novel proteins with the potential to become new therapies. Nvidia and partner Evozyne have new research showing that their technologies created novel proteins never before seen in nature, doing it faster and with better results. They did it by studying the language of life. Language learning models are now a hot discussion topic due to technologies such as ChatGPT, AI software that analyzes language to answer questions and even engage in conversation with a user. Kimberly Powell, vice president of health care at Nvidia, says language learning techniques can also be applied to genomics, in particular proteins that are encoded by our genes. “We’ve learned that these large language models can understand relationships just through studying amino acid sequence,” Powell said. “There is information about protein function when you can encode and represent and explore that data in these large language models.” The research results were announced during the recent J.P. Morgan Healthcare Conference in San Francisco. Powell discussed them during a separate briefing with journalists. The novel proteins stem from a collaboration between Nvidia and Evozyne, a Chicago-based protein design startup. Neither company develops new drugs but their technologies are used by biotech and pharmaceutical companies working in drug discovery. Nvidia and Evozyne began working together in 2022, collaborating to develop a new deep learning model that can learn the rules of protein function. Using those rules, they aimed to design new proteins with improved functions. The model was built on Nvidia’s technology for training and deploying large language models for biology. The Nvidia and Evozyne research focused on the phenylalanine hydroxylase (PAH) protein family. PAH is an enzyme needed to break down phenylalanine, an amino acid found in certain foods. PAH deficiency leads to a rare disorder called phenylketonuria (PKU), in which phenylalanine levels build up in the body and cause neurological impairment. Patients who have this inherited disorder manage it by maintaining a strict diet that avoids phenylalanine-containing food. When engineering therapeutic proteins, scientists aim to make change that enhance the protein’s function without compromising its safety. In the research described by Nvidia, Evozyne was able to create a PAH protein with 51 mutations. Despite all of those changes, that protein was still able to achieve a two-and-a-half times enhancement in functionality compared to native human PAH, Powell said. Going further, the technology was able to design a PAH protein with 167 mutations. Despite changing more than half of the protein, that version of PAH still retained its function. PKU has few FDA-approved therapies. BioMarin Pharmaceutical markets two: the small molecule drug Kuvan, and Palynziq, an engineered enzyme designed to substitute for the deficient PAH. But the use of these drugs does not eliminate the need for patients to continue dietary restrictions. BioMarin is also developing a gene therapy that offers the potential for a one-time treatment of the enzyme deficiency. Other companies are in various stages of development with potential PKU therapies that could help the patients who don’t respond to the currently available BioMarin products. Homology Medicines is in early-stage clinical testing of a gene-editing therapy that replaces the disease-causing gene with a functional one. PTC Therapeutics has reached late-stage clinical testing with a small molecule drug for PKU. Earlier this month, Jnana Therapeutics received FDA permission to begin a Phase 1 trial of a small molecule drug candidate for the metabolic disorder. Powell said the results from Nvidia and Evozyne are promising for the design of novel protein therapies. Protein engineering methods used today include directed evolution, an approach that makes iterative changes until achieving the protein with the desired features and functions. She said directed evolution would have taken months, perhaps even years to achieve what Evozyne did to design its novel PAH proteins. The startup is calling its approach machine learning-guided protein engineering. “With this ability for us to explore an essentially infinite space of proteins, to now be able to find the proteins with the function you desire while maintaining other properties that you also desire, like the safety of the proteins, that’s what these methods are absolutely unlocking,” Powell said. Image by Nvidia

临床1期

2022-07-12

·生物谷

JITC：南京医科大学团队发布肝癌新辅助临床研究成果

据统计，2020年，全球范围内肝癌发病率排在所有恶性肿瘤的第7位，但肝癌相关死亡率却排在第2位，死亡率排名远超发病率，提示肝癌的治疗任重而道远[1]。据统计，2020年，全球范围内肝癌发病率排在所有恶性肿瘤的第7位，但肝癌相关死亡率却排在第2位，死亡率排名远超发病率，提示肝癌的治疗任重而道远[1]。肝细胞肝癌（HCC）是肝癌的主要类型，手术切除是重要的治疗手段之一。大约40%的HCC患者在诊断时即为局部晚期（根据中国肝癌分期标准为IIb/IIIa期），按照欧洲和美国肝癌协会标准，这一部分患者已经丧失手术切除机会。但在中国，对于局部晚期HCC患者，如果符合一定条件可以接受手术切除治疗[2, 3]。不幸的是，大约55%的接受手术切除+术后辅助治疗的HCC患者，在术后中位22个月的时候肿瘤复发。新辅助治疗可提高多种恶性肿瘤的手术切除率，可能给原本不能切除的恶性肿瘤带来手术的机会，这已成为医学界共识，但在肝癌围手术期系统性治疗（辅助治疗/新辅助治疗）方面，目前很少有相关研究报道。临床前研究发现，免疫治疗联合抗血管治疗具有协同效应。IMbrave150研究发现阿替利珠单抗联合贝伐珠单抗与索拉非尼单药相比，可以改善不可切除HCC患者无进展生存时间（PFS）和总生存时间（OS）[4]。KEYNOTE-524研究发现帕博利珠单抗联合仑伐替尼在不可切除HCC患者中，可达到46%的客观缓解率（ORR）[5]。虽然免疫治疗联合抗血管治疗在不可切除HCC患者中获得了一定疗效，但在可切除肝癌方面，目前仅有少数研究报道。比如纳武利尤单抗联合cabozantinib用于局部晚期可切除HCC新辅助治疗，切缘阴性率达80%，主要病理缓解率（MPR）为42%。卡瑞利珠单抗目前已批准用于HCC治疗，阿帕替尼在肝癌中也具有一定的疗效。RESCUE研究发现，两者联合在晚期HCC中达到了34.4%的ORR和5.7个月的中位PFS[6]。为进一步研究卡瑞利珠单抗联合阿帕替尼在可切除HCC中的的疗效和安全性，南京医科大学第一附属医院夏永祥、王学浩、王平和浦立勇等领衔的研究团队，开展了一项开放标签、单臂、Ⅱ期临床研究[7]。他们发现，卡瑞利珠单抗联合阿帕替尼在可切除HCC新辅助治疗中，展示出颇有前景的疗效和可控的安全性。研究还发现树突状细胞浸润可作为预测卡瑞利珠单抗联合阿帕替尼新辅助治疗疗效和患者复发的生物标志物，循环肿瘤DNA可作为预测病理缓解及复发的生物标志物。对部分多病灶HCC患者，不同病灶对治疗的敏感性存在差异。异常的糖代谢与不同病灶对于治疗的敏感性相关。研究者认为小剂量新辅助治疗结合术后辅助治疗对抑制肝癌复发有一定作用，低强度的新辅助治疗后患者病灶病理反应率较低，联合术后辅助治疗对于改善该低病理反应非常必要。这一研究成果发表在著名期刊Journal for ImmunoTherapy of Cancer上。论文首页截图在2019年12月至2022年6月期间，这个研究共招募了20名可切除HCC患者。最终只有18名患者入组研究，他们的平均年龄54.7岁，大部分为男性。根据巴塞罗那临床肝癌分期（BCLC），5名（27.8%）患者为B期，13名（72.2%）患者为C期。这18名患者接受了3个周期的卡瑞利珠单抗+阿帕替尼新辅助治疗，完成治疗后46天，17名患者接受手术治疗，1名患者因肿瘤进展未进行手术。术后4周内，13名患者接受卡瑞利珠单抗+阿帕替尼辅助治疗，其余4名患者未接受辅助治疗（1名患者为肝细胞-胆管细胞混合型肝癌，2名患者未达到R0切除，1名患者因其他原因未接受辅助治疗）。研究流程图及研究终点研究的主要终点为MPR（定义为肿瘤切除后病理切片显示肿瘤坏死部分达到90%–99%），次要终点为pCR（定义为肿瘤切除后病理切片显示无任何肿瘤残留）。先来看疗效，18名完成新辅助治疗的患者中，根据RECIST1.1标准，有3名（16.7%）患者达到客观缓解，根据mRECIST1.1标准，有6名（33.3%）患者达到客观缓解。在17名接受手术治疗的患者中，3名（16.7%）患者达到MPR，1名（5.9%）患者达到pCR。在基线甲胎蛋白（AFP）升高的8名患者中，2名患者接受新辅助治疗后，AFP水平显著下降。安全性方面，18名接受新辅助治疗的患者被纳入安全分析集，16名（88.9%）患者出现了至少一次治疗相关不良事件（TRAE），最常见的TRAE依次为发热，高血压、乳酸脱氢酶水平升高和腹痛。3名（16.7%）患者出现了3级及以上TRAE，最常见的依次为皮疹、高血压、药物性肝损伤、中性粒细胞缺乏症。 13名完成全部治疗的患者接受了随访，结果显示1年的RFS率为53.85%，pCR患者RFS率高于non-pCR患者，但未达统计学显著性差异，单病灶患者RFS率高于多病灶患者，可能因为样本量较小，P值也未达到统计学显著性差异标准。值得一提的是，8名单病灶HCC患者中仅有2名患者出现复发，而其他研究中，未接受新辅助治疗的可切除肝癌患者复发率远高于该研究。根据患者手术切除标本中肿瘤细胞坏死比例，将患者分为有反应组（R组，定义为肿瘤细胞坏死比例≥50%），和无反应组（NR组，定义为肿瘤细胞坏死比例＜50%）。通过对治疗前肿瘤组织中289个免疫相关基因的转录数据分析，研究人员发现，R组与NR组相比，CCL13，MLANA，TNFSF9，IDO1，CD70，IL12RB2，CD19和IL4基因转录水平升高，而HILA-DQ1和GUSB基因的转录水平降低。免疫相关基因转录水平和新辅助治疗疗效的关系随后，研究人员分析了肿瘤微环境免疫细胞浸润分数，他们发现，R组免疫细胞浸润得分更高，特别是树突状细胞得分显著高于NR组，提示树突状细胞浸润水平可作为HCC新辅助治疗疗效生物标志物。此外，研究人员还发现R0切除患者较R1切除患者，ctDNA阳性率明显降低。ctDNA阳性患者RFS较ctDNA阴性的患者显著缩短。患者接受辅助治疗后，ctDNA显著下降患者RFS长于ctDNA没有明显下降患者。根据不同病灶对新辅助治疗的反应，研究人员还将肿瘤分为R病灶和NR病灶（R病灶定义为肿瘤细胞坏死比例≥50%的肿瘤病灶。NR病灶定义为肿瘤细胞坏死比例＜50%的肿瘤病灶）。通过对R病灶和NR病灶蛋白组学进行分析，他们发现NR病灶中，PCBD1，TPI1，C1QA，FLAD1蛋白表达显著升高，而R病灶中，FASN，TCP1，PKM蛋白表达显著升高。通过KEGG通路富集分析发现，这些表达改变的蛋白显著富集到“糖酵解”和“甘露糖代谢”通路。 R病灶和NR病灶蛋白组学差异最后，研究者认为本研究为小样本Ⅱ期临床研究，存在一定的局限性，且研究的随访时间仅1年，研究中治疗的选择需要依据临床经验进行调整和改进。基于患者标本的RNA水平、DNA水平、蛋白水平等数据，初步探索了新辅助治疗耐药的原因，但是目前研究尚较表浅，需要更深入研究探索其机制。总的来说，卡瑞利珠单抗联合阿帕替尼在可切除HCC新辅助治疗中，展示出颇有前景的疗效，且安全性可控。参考文献: 1, Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209–49. 2, Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American association for the study of liver diseases. Hepatology 2018;68:723–50. 3, Zhou J, Sun H-C, Wang Z, et al. Guidelines for diagnosis and treatment of primary liver cancer in China (2017 edition). Liver Cancer 2018;7:235–60. 4, Qin S, Ren Z, Feng Y-H, et al. Atezolizumab plus bevacizumab versus sorafenib in the Chinese subpopulation with unresectable hepatocellular carcinoma: phase 3 randomized, open-label IMbrave150 study. Liver Cancer 2021;10:296–308. 5, Finn RS, Ikeda M, Zhu AX, et al. Phase Ib study of Lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. J Clin Oncol 2020;38:2960–70. 6, Xu J, Shen J, Gu S, et al. Camrelizumab in combination with apatinib in patients with advanced hepatocellular carcinoma (RESCUE): a nonrandomized, open-label, phase II trial. Clin Cancer Res 2021;27:1003–11. 7, Xia Y, Tang W, Qian X, et al.Efficacy and safety of camrelizumab plus apatinib during the perioperative period in resectable hepatocellular carcinoma: a single-arm, open label, phase II clinical trialJournal for ImmunoTherapy of Cancer 2022;10:e004656. doi: 10.1136/jitc-2022-004656.