About

Yi Tang received his undergraduate degree in Chemical Engineering and Material Science from Penn State University. He earned his Ph.D. in Chemical Engineering from the California Institute of Technology under the guidance of Prof. David A. Tirrell. Following NIH postdoctoral training in Chemical Biology with Prof. Chaitan Khosla at Stanford University, he started his independent career at UCLA in 2004. He is currently the Chancellor Professor in the Department of Chemical and Biomolecular Engineering at UCLA, with joint appointments in the Department of Chemistry and Biochemistry and the Department of Bioengineering. His research interests focus on natural product biosynthesis and biocatalysis. His lab aims to elucidate biosynthetic pathways of polyketides, nonribosomal peptides, and related compounds, studying the biochemical and structural basis of enzymes involved. They are particularly interested in the biosynthesis of aromatic polyketides from Streptomyces and compounds from filamentous fungi, with goals of engineering biosynthesis of unnatural natural products through combinatorial biosynthesis. In biocatalysis, his team works on discovering and engineering enzymes for pharmaceutical synthesis, demonstrating approaches such as the biocatalytic production of drugs like simvastatin. Recently, his research has expanded into nanotechnology, biomaterials, and drug delivery, focusing on efficient delivery of biological molecules for applications in cancer therapy, imaging, vaccination, and reprogramming, often in collaboration with other labs.

Research topics

• Biology
• Biochemistry
• Computational biology
• Genetics
• Chemistry
• Organic chemistry
• Stereochemistry
• Nanotechnology
• Materials science
• Mathematics

Selected publications

• Abstract 4965: Sarcomatoid transformation rewires the immune spatial landscape and checkpoint regulation in chromophobe renal cell carcinoma

  Cancer Research · 2026-04-03

  article

  Abstract Background: Chromophobe renal cell carcinoma (ChRCC) is the second most common non-clear cell RCC. Patients with metastatic ChRCC have a poor prognosis with a median overall survival of ∼2 years. Sarcomatoid transformation occurs in ∼5% of ChRCC and is associated with increased metastatic risk and reduced survival. In clear cell RCC, the sarcomatoid phenotype is associated with an immune-inflamed state and enhanced responsiveness to immunotherapy. The immune landscape of sarcomatoid ChRCC and how it differs from classic ChRCC remain poorly defined. To address this, we performed a spatial comparison of the immune microenvironment in classic versus sarcomatoid ChRCC. Results: The 10x Genomics Xenium Prime Assay with 5k-plex target panels was performed on 10 ChRCC tumors (5 classic and 5 sarcomatoid). Hallmark pathway enrichment and differential expression analysis of pseudo-bulk data showed that sarcomatoid transformation is associated with activation of epithelial-mesenchymal transition, proliferation, and inflammatory response pathways (p < 0.05). Examining the spatial distribution of single cells, classic tumors showed an immune-excluded microenvironment, with T cells and macrophages localized to the tumor periphery. In contrast, sarcomatoid tumors exhibited an immune-infiltrated microenvironment, with T cells and macrophages present within the tumor bed. Sarcomatoid tumors showed an upregulation of CTLA4 across multiple T cell subsets, including cytotoxic CD8+ T cells, naïve T cells, and regulatory T cells, compared to classic tumors. Additionally, in sarcomatoid tumors, cytotoxic CD8+ T cells exhibited increased expression of LAG3 compared to classic tumors. Using metastasis as a proxy for sarcomatoid transformation, we compared 113 primary ChRCC tumors and 27 metastatic ChRCC tumors using bulk RNA-seq (Tempus xR). Expression profiles and immune deconvolution showed a shift from the immune-excluded, indolent primary state to an immune-modulated metastatic state marked by increased gamma delta T-cell abundance, higher LAG3 expression and decreased T cell exhaustion score (FDR < 0.05). Conclusion: By generating the first spatially resolved immune map of ChRCC, we showed that sarcomatoid ChRCC exhibits an immune-infiltrated microenvironment with intra-tumoral T cells and macrophages, accompanied by increased expression of immune checkpoint genes including, but not limited to CTLA4 and LAG3. This higher CTLA4 is of interest given the SUNNIFORECAST trial result, where combined CTLA4 and PD1 blockade achieved a 27% objective response rate in ChRCC. We also show that metastatic progression is associated with a shift toward a gamma delta T cell-enriched immune state. Together, these findings reveal potential therapeutic vulnerabilities and support further evaluation of immune checkpoint blockade in ChRCC. Citation Format: Wafaa Bzeih, Yan Tang, Tiegang Han, Andrew J. Sedgewick, Nathan D. Maulding, Carmen Priolo, Katrina Collins, Hadi Mansour, Joelle Chami, Michelle M. Stein, Justin Guinney, Michel Alchoueiry, Jessica F. Williams, Michelle S. Hirsch, Pavlos Msaouel, Elizabeth P. Henske. Sarcomatoid transformation rewires the immune spatial landscape and checkpoint regulation in chromophobe renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4965.

  PublisherDOI

• Nanobody-based bioPROTAC for viral protein degradation provides an antiviral strategy for porcine arterivirus

  Journal of Nanobiotechnology · 2026-04-05

  articleOpen access

  Proteolysis-targeting chimeras (PROTACs) are powerful tools for targeted protein degradation and are expected to contribute to a promising strategy for next-generation precision therapeutic antiviral drug development. Nanobody-based bioPROTACs can directly bind to protein and mediate target protein degradation, providing a potential antiviral strategy for RNA viruses featuring error-prone replication. Here, we aimed to establish a modular speckle-type POZ protein (SPOP)-derived bioPROTAC platform that enabled rapid antiviral drug construction through the substitution of a target protein-specific nanobody. Using porcine reproductive and respiratory syndrome virus (PRRSV) as a model pathogen, bioPROTACs molecules were successfully constructed by flexibly fusing nanobodies against PRRSV nonstructural protein 9 (Nsp9, viral RdRp) to the BTB domain of SPOP. BioPROTACs demonstrated specific degradation of target proteins in a dose-dependent manner, and a bivalent nanobody configuration enhanced the degradation efficiency to greater than 60%. BioPROTACs exhibited antiviral activity against multi-lineages of PRRSV and significantly potentiated the antiviral efficacy of non-neutralizing nanobodies in vitro. Furthermore, intravenous delivery of bioPROTAC-encoding constructs in mice achieved significant reduction of target protein levels within 24 h, demonstrating efficient in vivo degradation capability. Moreover, the combined administration of bioPROTACs via the mRNA-LNP system suppressed PRRSV proliferation and transmission in piglets, which was characterized by reduced viremia, alleviated lung damage, and a decrease in the piglet mortality rate to 25%. Importantly, we revealed that the subcellular localization of both the target protein and bioPROTACs determined the degradation pathway, confirming that cytoplasmic 9nb-SPOPΔNLS mediated Nsp9 degradation through the autophagy–lysosome pathway in the cytoplasm. This study expands the applicability of SPOP-derived bioPROTACs from nuclear proteins to cytoplasmic proteins, providing a novel strategy for developing antiviral therapies against highly variable viruses. The aim of the current study was to develop and validate modular bioPROTACs targeting essential viral proteins. We constructed the degraders by fusing target-specific nanobodies to the BTB domain of SPOP. More importantly, a combination of bioPROTACs targeting different stages of viral replication, delivered via mRNA-LNPs, suppressed viral replication in a pig model. These findings offer valuable insights into the target degradation mechanisms of SPOP-derived bioPROTACs and provide a foundation for the design of antivirals that have activity against multi-lineages of porcine arterivirus and overcome drug resistance.

  PublisherDOI

• A Mitochondrial Plasma Proteomic Signature Identifies Metastatic Chromophobe Renal Cell Carcinoma

  Cancers · 2026-03-23

  articleOpen access

  BACKGROUND: Chromophobe renal cell carcinoma (ChRCC) is characterized by the accumulation of abnormal mitochondria, a high rate of mitochondrial DNA (mtDNA) mutations, and altered oxidative metabolism. There are no existing circulating biomarkers to distinguish metastatic ChRCC from clear cell renal cell carcinoma (ccRCC). METHODS: High-throughput plasma proteomic profiling using the SomaScan platform was performed in 18 ChRCC (including 16 metastatic ChRCC) and 197 metastatic ccRCC patients. Data were harmonized to generate a unified 7K-protein matrix. RESULTS: Differential expression analysis was performed using limma (version 3.62.2). Of 7272 quantified human plasma proteins, 209 were differentially expressed between ChRCC and ccRCC. Upregulated proteins in ChRCC included essential β-oxidation enzymes such as ECH1 (enoyl-CoA hydratase 1) and ECI1 (enoyl-CoA delta-isomerase 1), suggesting increased long-chain fatty acid degradation. Creatine and energy-buffering pathways were also represented, with increased CKMT1A (Creatine Kinase, Mitochondrial 1A) in ChRCC. KIM-1 (Kidney Injury Molecule-1) and leptin were lower in ChRCC, consistent with the known upregulation of these proteins in ccRCC. Pathway enrichment analyses revealed an overrepresentation of mitochondrial protein degradation, fatty acid β-oxidation, and respiratory electron transport in ChRCC, suggesting that ChRCC sheds a unique mitochondrial signature into the peripheral circulation. A bootstrap-based LASSO logistic regression restricted to upregulated mitochondrial proteins in ChRCC vs. ccRCC consistently selected ECI1 and CKMT1A. The LASSO model achieved an AUROC of 0.964. CONCLUSIONS: Compared to ccRCC, the plasma proteome of metastatic ChRCC is dominated by mitochondrial metabolic enzymes, revealing a systemic metabolic phenotype strikingly aligned with the known histologic accumulation of abnormal mitochondria in ChRCC cells.

  PublisherOA PDFDOI

• Copper-dependent halogenase catalyses unactivated C−H bond functionalization

  Nature · 2025-01-29 · 29 citations

  articleOpen accessSenior authorCorresponding
  PublisherOA PDFDOI

• Genome Mining of Fungal Aza-Polycyclic Natural Products Derived from Arginine-Containing Cyclodipeptides

  Journal of Natural Products · 2025-06-09 · 3 citations

  articleOpen accessSenior authorCorresponding

  Arginine-containing cyclodipeptide synthases (RCDPSs) from fungi constitute a new family of tRNA-dependent enzymes that can biosynthesize cyclo-Arg-Xaa dipeptides. The incorporation of an arginine residue significantly expands the chemical space of guanidine-containing natural products. Here, we mined fungal biosynthetic gene clusters (BGCs) containing different RCDPS to discover aza-polycyclic natural products. The pno BGC from Aspergillus pseudonomius produced pentacyclic pyrroloindoline diketopiperazines (DKPs) of which the arginine side chain is oxidatively cyclized into a guanidino-proline. Two RCDPS-encoding BGCs, car and esh from Aspergillus carlsbadensis and Eupenicillium shearii, respectively, produced DKPs connected to five- and seven-membered spirocycles as a result of oxidative cyclization of the guanidino group catalyzed by α-ketoglutarate/Fe(II)-dependent oxygenases. The esh pathway involves a tandem cyclization and epimerization to generate the guanidino-bridged tricyclo-[3.31,2.2.2]-piperazinedione core. The aza-polycyclic structures characterized in this work demonstrate the potential of using RCDPS as a starting point for the discovery of new natural products.

  PublisherOA PDFDOI

• Combining MicroED and native mass spectrometry for structural discovery of enzyme–small molecule complexes

  Proceedings of the National Academy of Sciences · 2025-07-28 · 4 citations

  articleOpen access

  With the goal of accelerating the discovery of small molecule-protein complexes, we leverage fast, low-dose, event-based electron counting microcrystal electron diffraction (MicroED) data collection and native mass spectrometry. This approach, which we term electron diffraction with native mass spectrometry (ED-MS), allows assignment of protein target structures bound to ligands with data obtained from crystal slurries soaked with mixtures of known inhibitors and crude biosynthetic reactions. This extends to libraries of printed ligands dispensed directly onto TEM grids for later soaking with microcrystal slurries, and complexes with noncovalent ligands. ED-MS resolves structures of the natural product, epoxide-based cysteine protease inhibitor E-64, and its biosynthetic analogs bound to the model cysteine protease, papain. It further identifies papain binding to its preferred natural products, by showing that two analogs of E-64 outcompete others in binding to papain crystals, and by detecting papain bound to E-64 and an analog from crude biosynthetic reactions, without purification. ED-MS also resolves binding of the CTX-M-14 β-lactamase, a target of active drug development, to the non-β-lactam inhibitor, avibactam, alone or in a cocktail of unrelated compounds. These results illustrate the utility of ED-MS for natural product ligand discovery and for structure-based screening of small molecule binders to macromolecular targets, promising utility for drug discovery.

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• An antifungal with a novel mechanism of action discovered via resistance gene-guided genome mining

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-09 · 1 citations

  preprintOpen access

  Abstract Invasive fungal infections claim over two million lives annually, a problem exacerbated by rising resistance to current antifungal treatments and an increasing population of immunocompromised individuals. Despite this, antifungal drug development has stagnated, with few novel agents and fewer novel targets explored in recent decades. Here, we validate acetolactate synthase (ALS), an enzyme critical for branched-chain amino acid biosynthesis and absent in humans, as a promising target for new therapeutics. Using resistance gene-guided genome mining, we discovered a biosynthetic gene cluster in Aspergillus terreus encoding HB-35018 ( 1) , a novel spiro- cis -decalin tetramic acid that potently inhibits ALS. Biochemical and antifungal assays demonstrate that 1 surpasses existing ALS inhibitors in efficacy against Aspergillus fumigatus and other pathogenic fungi. Structural studies via cryo-electron microscopy reveal a unique covalent binding interaction between compound 1 and ALS, distinct from known inhibitors and finally, we demonstrate that ALS is essential for the virulence in a mouse model of invasive aspergillosis. These findings position ALS as a promising target for antifungal development and demonstrate the potential of resistance gene-guided genome mining for antifungal discovery.

  PublisherOA PDFDOI

• Genome Mining of Isoindolinone-Containing Peptide Natural Products

  Journal of the American Chemical Society · 2025-05-19 · 2 citations

  articleOpen accessSenior authorCorresponding

  Peptide natural products (PNPs) are important sources of bioactive compounds. Recent studies have shown that oligopeptides or pseudopeptides can be synthesized by amide-bond-forming enzymes such as ATP-grasp enzymes and amide-bond synthetases (ABSs). By focusing on ATP-grasp enzymes as part of a conserved biosynthetic enzyme ensemble, genome mining of PNPs was performed on three biosynthetic gene clusters (BGCs) from diverse fungi, including Coccidioides immitis RS, the causative agent of valley fever. We demonstrate that the conserved enzymes synthesize a common dipeptide fragment, l-leucine-l-O-isoindolinone-homoserine (l-Leu-l-Isd), which is modified and diversified into three PNPs (1–3) by associated enzymes in the three pathways. Pathway reconstitution and enzymatic assays led to the characterization of six ATP-grasp enzymes and ABSs that catalyze di-, tri-, and tetrapeptide formation. From the C. immitis BGC, a flavoenzyme catalyzing the direct oxidation of l-tryptophan to l-oxindolylalanine was discovered. Our work validates ATP-grasp enzymes and ABSs as leads to mine new PNPs and further showcases the biocatalytic potential of these enzymes in catalyzing amide-bond formation.

  PublisherOA PDFDOI

• Fungal RiPPs Side Chain Macrocyclization Catalyzed by Copper-Dependent DUF3328 Enzyme

  Journal of the American Chemical Society · 2025-03-03 · 22 citations

  articleOpen accessSenior authorCorresponding

  Fungal enzymes containing domain of unknown function (DUF) 3328 have been implicated in the oxidative maturation of ribosomally synthesized and post-translationally modified peptides (RiPPs). We report here the functional characterization of one such enzyme, AprY, involved in the biosynthesis of RiPP asperipin-2a. Biochemical reconstitution of AprY showed the enzyme catalyzes two consecutive C-O cross-linking reactions between tyrosines and beta-carbons of residues in the core hexapeptide. The side-chain macrocyclization activities of AprY are copper- and oxygen-dependent and do not require a leader peptide sequence.

  PublisherOA PDFDOI

• Copper-Dependent Hydroxylation Catalyzed by the DUF3328 Enzyme CctR

  Organic Letters · 2025-07-22 · 4 citations

  articleSenior authorCorresponding

  Enzymes containing domain of unknown function (DUF) 3328 are proposed to catalyze varied reactions in fungal natural product biosynthesis, including halogenation, hydroxylation, oxidative cyclization, etc. However, only two DUF3328 enzymes have been very recently characterized: halogenase ApnU and macrocyclase AprY. We report the biochemical characterization of CctR, a DUF3328 enzyme that catalyzes copper- and oxygen-dependent C(sp3)–H hydroxylation in hydroxycyclochlorotine biosynthesis. This work expands the catalytic repertoire of this widely distributed enzyme family.

  PublisherDOI

Recent grants

• Collaborative Research: SusChEM: A Robust Yeast Platform for the Synthesis and Engineering of Polyketide-Based Pharmaceuticals and Chemicals

  NSF · $300k · 2016–2019

• NIH Grant R21GM077264

  NIH · $401k · 2010

• Engineering Yeast towards High Titer Production of Monoterpene Indole Alkaloid Natural Products

  NIH · $3.6M · 2018–2028

• Rediscovering Natural Chemical Diversity

  NIH · $3.9M · 2012–2019

• Discovery and Characterization of SAM-Dependent Pericyclases

  NSF · $525k · 2018–2021

Frequent coauthors

• Kenji Watanabe

  56 shared

• Yit‐Heng Chooi

  University of Western Australia

  52 shared

• Wei Xu

  Fujian University of Traditional Chinese Medicine

  48 shared

• K. N. Houk

  University of California, Los Angeles

  39 shared

• Pin Wang

  University of Southern California

  36 shared

• Zhen Gu

  Zhejiang University

  34 shared

• M. Ohashi

  University of California, Los Angeles

  33 shared

• Man‐Cheng Tang

  Shanghai Jiao Tong University

  30 shared

Labs

• Yi Tang LabPI

Awards & honors

• American Institute of Chemical Engineers (AIChE) Allan P. Co…
• American Chemical Society (ACS) Biochemical Technology Divis…
• ACS Arthur C. Cope Scholar Award (2012)
• EPA Presidential Green Chemistry Challenge Award (2012)
• NIH DP1 Director Pioneer Award (2012)