Steven Duy Truong

All Publications

• PTER is a N-acetyltaurine hydrolase that regulates feeding and obesity. Nature Wei, W., Lyu, X., Markhard, A. L., Fu, S., Mardjuki, R. E., Cavanagh, P. E., Zeng, X., Rajniak, J., Lu, N., Xiao, S., Zhao, M., Moya-Garzon, M. D., Truong, S. D., Chou, J. C., Wat, L. W., Chidambaranathan-Reghupaty, S., Coassolo, L., Xu, D., Shen, F., Huang, W., Ramirez, C. B., Jang, C., Li, L., Svensson, K. J., Fischbach, M. A., Long, J. Z. 2024

  Abstract

  Taurine is a conditionally essential micronutrient and one of the most abundant amino acids in humans1-3. In endogenous taurine metabolism, dedicated enzymes are involved in the biosynthesis of taurine from cysteine and in the downstream metabolism of secondary taurine metabolites4,5. One taurine metabolite is N-acetyltaurine6. Levels of N-acetyltaurine are dynamically regulated by stimuli that alter taurine or acetate flux, including endurance exercise7, dietary taurine supplementation8 and alcohol consumption6,9. So far, the identities of the enzymes involved in N-acetyltaurine metabolism, and the potential functions of N-acetyltaurine itself, have remained unknown. Here we show that the body mass index associated orphan enzyme phosphotriesterase-related (PTER)10 is a physiological N-acetyltaurine hydrolase. In vitro, PTER catalyses the hydrolysis of N-acetyltaurine to taurine and acetate. In mice, PTER is expressed in the kidney, liver and brainstem. Genetic ablation of Pter in mice results in complete loss of tissue N-acetyltaurine hydrolysis activity and a systemic increase in N-acetyltaurine levels. After stimuli that increase taurine levels, Pter knockout mice exhibit reduced food intake, resistance to diet-induced obesity and improved glucose homeostasis. Administration of N-acetyltaurine to obese wild-type mice also reduces food intake and body weight in a GFRAL-dependent manner. These data place PTER into a central enzymatic node of secondary taurine metabolism and uncover a role for PTER and N-acetyltaurine in body weight control and energy balance.

  View details for DOI 10.1038/s41586-024-07801-6

  View details for PubMedID 39112712

  View details for PubMedCentralID 3501277

• Genome-wide association and polygenic risk score estimation of type 2 diabetes mellitus in Kinh Vietnamese-A pilot study. Journal of cellular and molecular medicine Mai, T. P., Luong, B. A., Ma, P. T., Tran, T. V., Dinh Ngo, T. T., Hoang, C. K., Van Tran, L., Le, B. H., Vu, H. A., Le, L. H., Le, K. T., Truong, S., Tran, N. Q., Do, M. D. 2024; 28 (13): e18526

  Abstract

  A genome-wide association study (GWAS) is a powerful tool in investigating genetic contribution, which is a crucial factor in the development of complex multifactorial diseases, such as type 2 diabetes mellitus. Type 2 diabetes mellitus is a major healthcare burden in the Western Pacific region; however, there is limited availability of genetic-associated data for type 2 diabetes in Southeast Asia, especially among the Kinh Vietnamese population. This lack of information exacerbates global healthcare disparities. In this study, 997 Kinh Vietnamese individuals (503 with type 2 diabetes and 494 controls) were prospectively recruited and their clinical and paraclinical information was recorded. DNA samples were collected and whole genome genotyping was performed. Standard quality control and genetic imputation using the 1000 Genomes database were executed. A polygenic risk score for type 2 diabetes was generated in different models using East Asian, European, and mix ancestry GWAS summary statistics as training datasets. After quality control and genetic imputation, 107 polymorphisms reached suggestive statistical significance for GWAS (≤5 × 10-6) and rs11079784 was one of the potential markers strongly associated with type 2 diabetes in the studied population. The best polygenic risk score model predicting type 2 diabetes mellitus had AUC = 0.70 (95% confidence interval = 0.62-0.77) based on a mix of ancestral GWAS summary statistics. These data show promising results for genetic association with a polygenic risk score estimation in the Kinh Vietnamese population; the results also highlight the essential role of population diversity in a GWAS of type 2 diabetes mellitus.

  View details for DOI 10.1111/jcmm.18526

  View details for PubMedID 38957036

  View details for PubMedCentralID PMC11220366

• A PTER-dependent pathway of taurine metabolism linked to energy balance. bioRxiv : the preprint server for biology Wei, W., Lyu, X., Markhard, A. L., Fu, S., Mardjuki, R. E., Cavanagh, P. E., Zeng, X., Rajniak, J., Lu, N., Xiao, S., Zhao, M., Moya-Garzon, M. D., Truong, S. D., Chou, J. C., Wat, L. W., Chidambaranathan-Reghupaty, S., Coassolo, L., Xu, D., Shen, F., Huang, W., Ramirez, C. B., Jang, C., Svensson, K. J., Fischbach, M. A., Long, J. Z. 2024

  Abstract

  Taurine is a conditionally essential micronutrient and one of the most abundant amino acids in humans1-3. In endogenous taurine metabolism, dedicated enzymes are involved in biosynthesis of taurine from cysteine as well as the downstream derivatization of taurine into secondary taurine metabolites4,5. One such taurine metabolite is N-acetyltaurine6. Levels of N-acetyltaurine are dynamically regulated by diverse physiologic perturbations that alter taurine and/or acetate flux, including endurance exercise7, nutritional taurine supplementation8, and alcohol consumption6,9. While taurine N-acetyltransferase activity has been previously detected in mammalian cells6,7, the molecular identity of this enzyme, and the physiologic relevance of N-acetyltaurine, have remained unknown. Here we show that the orphan body mass index-associated enzyme PTER (phosphotriesterase-related)10 is the principal mammalian taurine N-acetyltransferase/hydrolase. In vitro, recombinant PTER catalyzes bidirectional taurine N-acetylation with free acetate as well as the reverse N-acetyltaurine hydrolysis reaction. Genetic ablation of PTER in mice results in complete loss of tissue taurine N-acetyltransferase/hydrolysis activities and systemic elevation of N-acetyltaurine levels. Upon stimuli that increase taurine levels, PTER-KO mice exhibit lower body weight, reduced adiposity, and improved glucose homeostasis. These phenotypes are recapitulated by administration of N-acetyltaurine to wild-type mice. Lastly, the anorexigenic and anti-obesity effects of N-acetyltaurine require functional GFRAL receptors. Together, these data uncover enzymatic control of a previously enigmatic pathway of secondary taurine metabolism linked to energy balance.

  View details for DOI 10.1101/2024.03.21.586194

  View details for PubMedID 38562797

  View details for PubMedCentralID PMC10983888

• Determination of the Structure and Dynamics of the Fuzzy Coat of an Amyloid Fibril of IAPP Using Cryo-Electron Microscopy. Biochemistry Faidon Brotzakis, Z., Lohr, T., Truong, S., Hoff, S., Bonomi, M., Vendruscolo, M. 2023

  Abstract

  In recent years, major advances in cryo-electron microscopy (cryo-EM) have enabled the routine determination of complex biomolecular structures at atomistic resolution. An open challenge for this approach, however, concerns large systems that exhibit continuous dynamics. To address this problem, we developed the metadynamic electron microscopy metainference (MEMMI) method, which incorporates metadynamics, an enhanced conformational sampling approach, into the metainference method of integrative structural biology. MEMMI enables the simultaneous determination of the structure and dynamics of large heterogeneous systems by combining cryo-EM density maps with prior information through molecular dynamics, while at the same time modeling the different sources of error. To illustrate the method, we apply it to elucidate the dynamics of an amyloid fibril of the islet amyloid polypeptide (IAPP). The resulting conformational ensemble provides an accurate description of the structural variability of the disordered region of the amyloid fibril, known as fuzzy coat. The conformational ensemble also reveals that in nearly half of the structural core of this amyloid fibril, the side chains exhibit liquid-like dynamics despite the presence of the highly ordered network backbone of hydrogen bonds characteristic of the cross-beta structure of amyloid fibrils.

  View details for DOI 10.1021/acs.biochem.3c00010

  View details for PubMedID 37477459

• Association of KCNJ11 and ABCC8 single-nucleotide polymorphisms with type 2 diabetes mellitus in a Kinh Vietnamese population. Medicine Tran, N. Q., Truong, S. D., Ma, P. T., Hoang, C. K., Le, B. H., Dinh, T. T., Van Tran, L., Tran, T. V., Le, L. H., Le, K. T., Nguyen, H. T., Vu, H. A., Mai, T. P., Do, M. D. 2022; 101 (46): e31653

  Abstract

  Type 2 diabetes mellitus (T2DM) is a genetically influenced disease, but few studies have been performed to investigate the genetic basis of T2DM in Vietnamese subjects. Thus, the potential associations of KCNJ11 and ABCC8 single nucleotide polymorphisms (SNPs) with T2DM were investigated in a Kinh Vietnamese population. A cross-sectional study consisting of 404 subjects including 202 T2DM cases and 202 non-T2DM controls was designed to examine the potential associations of 4 KCNJ11 and ABCC8 SNPs (rs5219, rs2285676, rs1799859, and rs757110) with T2DM. Genotypes were identified based on restriction fragment length polymorphism and tetra-primer amplification refractory mutation system polymerase chain reaction. After statistically adjusting for age, sex, and BMI, rs5219 was found to be associated with an increased risk of T2DM under 2 inheritance models: codominant (OR = 2.15, 95% confidence intervals [CI] = 1.09-4.22) and recessive (OR = 2.08, 95%CI = 1.09-3.94). On the other hand, rs2285676, rs1799859, and rs757110 were not associated with an increased risk of T2DM. Haplotype analysis elucidated a strong linkage disequilibrium between the 3 SNPs, rs5219, rs2285676, and rs757110. The haplotype rs5219(A)/rs2285676(T)/rs757110(G) was associated with an increased risk of T2DM (OR = 1.42, 95%CI = 1.01-1.99). The results show that rs5219 is a lead candidate SNP associated with an increased risk of developing T2DM in the Kinh Vietnamese population. Further functional characterization is needed to uncover the mechanism underlying the potential genotype-phenotype associations.

  View details for DOI 10.1097/MD.0000000000031653

  View details for PubMedID 36401380

• Correlation between the binding affinity and the conformational entropy of nanobody SARS-CoV-2 spike protein complexes. Proceedings of the National Academy of Sciences of the United States of America Mikolajek, H., Weckener, M., Brotzakis, Z. F., Huo, J., Dalietou, E. V., Le Bas, A., Sormanni, P., Harrison, P. J., Ward, P. N., Truong, S., Moynie, L., Clare, D. K., Dumoux, M., Dormon, J., Norman, C., Hussain, N., Vogirala, V., Owens, R. J., Vendruscolo, M., Naismith, J. H. 2022; 119 (31): e2205412119

  Abstract

  Camelid single-domain antibodies, also known as nanobodies, can be readily isolated from naïve libraries for specific targets but often bind too weakly to their targets to be immediately useful. Laboratory-based genetic engineering methods to enhance their affinity, termed maturation, can deliver useful reagents for different areas of biology and potentially medicine. Using the receptor binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and a naïve library, we generated closely related nanobodies with micromolar to nanomolar binding affinities. By analyzing the structure-activity relationship using X-ray crystallography, cryoelectron microscopy, and biophysical methods, we observed that higher conformational entropy losses in the formation of the spike protein-nanobody complex are associated with tighter binding. To investigate this, we generated structural ensembles of the different complexes from electron microscopy maps and correlated the conformational fluctuations with binding affinity. This insight guided the engineering of a nanobody with improved affinity for the spike protein.

  View details for DOI 10.1073/pnas.2205412119

  View details for PubMedID 35858383

  View details for PubMedCentralID PMC9351521

• Association of ADIPOQ Single-Nucleotide Polymorphisms with the Two Clinical Phenotypes Type 2 Diabetes Mellitus and Metabolic Syndrome in a Kinh Vietnamese Population DIABETES METABOLIC SYNDROME AND OBESITY-TARGETS AND THERAPY Truong, S., Nam Quang Tran, Phat Tung Ma, Chi Khanh Hoang, Bao Hoang Le, Thang Dinh, Luong Tran, Thang Viet Tran, Linh Hoang Gia Le, Hoang Anh Vu, Thao Phuong Mai, Minh Duc Do 2022; 15: 307-319

  Abstract

  Genetic factors play an important role in the development of type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS). However, few genetic association studies related to these disorders have been performed with Vietnamese subjects. In this study, the potential associations of ADIPOQ single nucleotide polymorphisms (SNPs) with T2DM and MetS in a Kinh Vietnamese population were investigated.A study with 768 subjects was conducted to examine the associations of four ADIPOQ SNPs (rs266729, rs1501299, rs3774261, and rs822393) primarily with T2DM and secondarily with MetS. The TaqMan SNP genotyping assay was used to determine genotypes from subjects' DNA samples.After statistical adjustment for age, sex, and body mass index, the ADIPOQ SNP rs266729 was found to be associated with increased risk of T2DM under multiple inheritance models: codominant (OR = 2.30, 95% CI = 1.16-4.58), recessive (OR = 2.17, 95% CI = 1.11-4.26), and log-additive (OR = 1.32, 95% CI = 1.02-1.70). However, rs1501299, rs3774261, and rs822393 were not associated with risk for T2DM. Additionally, rs266729, rs3774261, and rs822393 were statistically associated with MetS, while rs1501299 was not. Haplotype analysis showed a strong linkage disequilibrium between the SNP pairs rs266729/rs822393 and rs1501299/rs3774261, and the haplotype rs266729(G)/rs822393(T) was not statistically associated with MetS.The results show that rs266729 is a lead candidate SNP associated with increased risk of developing T2DM and MetS in a Kinh Vietnamese population, while rs3774261 is associated with MetS only. Further functional characterization is needed to uncover the mechanism underlying the potential genotype-phenotype associations.

  View details for DOI 10.2147/DMSO.S347830

  View details for Web of Science ID 000751781400004

  View details for PubMedID 35140489

  View details for PubMedCentralID PMC8820255