The Transporter Classification Database (TCDB), freely accessible at http://www.tcdb.org, is a relational database containing sequence, structural, functional and evolutionary information about transport systems from a variety of living organisms, based on the International Union of Biochemistry and Molecular Biology-approved transporter classification (TC) system. It is a curated repository for factual information compiled largely from published references. It uses a functional/phylogenetic system of classification, and currently encompasses about 5000 representative transporters and putative transporters in more than 500 families. We here describe novel software designed to support and extend the usefulness of TCDB. Our recent efforts render it more user friendly, incorporate machine learning to input novel data in a semiautomatic fashion, and allow analyses that are more accurate and less time consuming. The availability of these tools has resulted in recognition of distant phylogenetic relationships and tremendous expansion of the information available to TCDB users.

/pdf/the-transporter-classification-database-recent-advances-52nj3625a8.pdf

The Transporter Classification Database: recent advances

The Transporter Classification Database (TCDB; http://www.tcdb.org) serves as a common reference point for transport protein research. The database contains more than 10 000 non-redundant proteins that represent all currently recognized families of transmembrane molecular transport systems. Proteins in TCDB are organized in a five level hierarchical system, where the first two levels are the class and subclass, the second two are the family and subfamily, and the last one is the transport system. Superfamilies that contain multiple families are included as hyperlinks to the five tier TC hierarchy. TCDB includes proteins from all types of living organisms and is the only transporter classification system that is both universal and recognized by the International Union of Biochemistry and Molecular Biology. It has been expanded by manual curation, contains extensive text descriptions providing structural, functional, mechanistic and evolutionary information, is supported by unique software and is interconnected to many other relevant databases. TCDB is of increasing usefulness to the international scientific community and can serve as a model for the expansion of database technologies. This manuscript describes an update of the database descriptions previously featured in NAR database issues.

https://escholarship.org/content/qt3nq310vs/qt3nq310vs.pdf?t=oldijy

The Transporter Classification Database

The determination of the crystal structures of small-molecule transporters has shed light on the conformational changes that take place during structural isomerization from outward- to inward-facing states. Rather than using a simple rocking movement of two bundles around a central substrate-binding site, it has become clear that even the most simplistic transporters utilize rearrangements of nonrigid bodies. In the most dramatic cases, one bundle is fixed while the other, structurally divergent, bundle carries the substrate some 18 A across the membrane, which in this review is termed an elevator alternating-access mechanism. Here, we compare and contrast rocker-switch, rocking-bundle, and elevator alternating-access mechanisms to highlight shared features and novel refinements to the basic alternating-access model.

Shared Molecular Mechanisms of Membrane Transporters

Wastewater effluents from mines and metal refineries are often contaminated with heavy metal ions, so they pose hazards to human and environmental health. Conventional technologies to remove heavy metal ions are well-established, but the most popular methods have drawbacks: chemical precipitation generates sludge waste, and activated carbon and ion exchange resins are made from unsustainable non-renewable resources. Using microbial biomass as the platform for heavy metal ion removal is an alternative method. Specifically, bioaccumulation is a natural biological phenomenon where microorganisms use proteins to uptake and sequester metal ions in the intracellular space to utilize in cellular processes (e.g., enzyme catalysis, signaling, stabilizing charges on biomolecules). Recombinant expression of these import-storage systems in genetically engineered microorganisms allows for enhanced uptake and sequestration of heavy metal ions. This has been studied for over two decades for bioremediative applications, but successful translation to industrial-scale processes is virtually non-existent. Meanwhile, demands for metal resources are increasing while discovery rates to supply primary grade ores are not. This review re-thinks how bioaccumulation can be used and proposes that it can be developed for bioextractive applications-the removal and recovery of heavy metal ions for downstream purification and refining, rather than disposal. This review consolidates previously tested import-storage systems into a biochemical framework and highlights efforts to overcome obstacles that limit industrial feasibility, thereby identifying gaps in knowledge and potential avenues of research in bioaccumulation.

/pdf/heavy-metal-removal-by-bioaccumulation-using-genetically-2wlpsi44yo.pdf

Heavy Metal Removal by Bioaccumulation Using Genetically Engineered Microorganisms.

The activation of nuclear factor-kappaB (NFκB), a proinflammatory transcription factor, is a commonly observed phenomenon in breast cancer. It facilitates the development of a hormone-independent, invasive, high-grade, and late-stage tumor phenotype. Moreover, the commonly used cancer chemotherapy and radiotherapy approaches activate NFκB, leading to the development of invasive breast cancers that show resistance to chemotherapy, radiotherapy, and endocrine therapy. Inhibition of NFκB results in an increase in the sensitivity of cancer cells to the apoptotic effects of chemotherapeutic agents and radiation and restoring hormone sensitivity, which is correlated with increased disease-free survival in patients with breast cancer. In this review article, we focus on the role of the NFκB signaling pathways in the development and progression of breast cancer and the validity of NFκB as a potential target for breast cancer prevention and therapy. We also discuss the recent findings that NFκB may have tumor suppressing activity in certain cancer types. Finally, this review also covers the state-of-the-art development of NFκB inhibitors for cancer therapy and prevention, the challenges in targeting validation, and pharmacology and toxicology evaluations of these agents from the bench to the bedside.

Targeting the NFκB signaling pathways for breast cancer prevention and therapy.

Visual rhodopsins are recognized members of the large and diverse family of G protein-coupled receptors (GPCRs), but their evolutionary origin and relationships to other proteins are not known. In a previous paper [Shlykov MA, Zheng WH, Chen JS & Saier MH Jr (2012) Biochim Biophys Acta 1818, 703-717], we characterized the 4-toluene sulfonate uptake permease (TSUP) family of transmembrane proteins, and showed that these 7-transmembrane segment (TMS) or 8-TMS proteins arose by intragenic duplication of a gene encoding a 4-TMS protein, sometimes followed by loss of a terminal TMS. In this study, we show that the TSUP, GPCR and microbial rhodopsin families are related to each other and to six other currently recognized transport protein families. We designate this superfamily the transporter/opsin/G protein-coupled receptor (TOG) superfamily. Despite their 8-TMS origins, the members of most constituent families exhibit 7-TMS topologies that are well conserved, and these arose by loss of either the N-terminal TMS (more frequent) or the C-terminal TMS (less frequent), depending on the family. Phylogenetic analyses revealed familial relationships within the superfamily and protein relationships within each of the nine families. The results of the statistical analyses leading to the conclusion of homology were confirmed using hidden Markov models, Pfam and 3D superimpositions. Proteins functioning by dissimilar mechanisms (channels, primary active transporters, secondary active transporters, group translocators and receptors) are interspersed on a phylogenetic tree of the TOG superfamily, suggesting that changes in the transport and energy-coupling mechanisms occurred multiple times during evolution of this superfamily.

/pdf/the-transporter-opsin-g-protein-coupled-receptor-tog-7khhda0oma.pdf

The transporter-opsin-G protein-coupled receptor (TOG) superfamily.

NKG2D ligands are cell surface proteins that activate NKG2D, a receptor used by natural killer (NK) cells to detect virus-infected and transformed cells. When tumour cells express high levels of NKG2D ligands, they are rejected by the immune system. Hence, reagents that increase NKG2D ligand expression on tumour cells can be important for tumour immunotherapy. To identify genes that regulate the NKG2D ligand H60a, we performed a microarray analysis of 3'-methylcholanthrene-induced sarcoma cell lines expressing high versus low H60a levels. A20, an inhibitor of nuclear factor-κB (NF-κB) activation, was differentially expressed in H60a-hi sarcoma cells. Correspondingly, treatment of tumour cells with inhibitors of NF-κB activation, such as sulfasalazine (slz), BAY-11-7085, or a non-phosphorylatable IκB, led to increased levels of H60a protein, whereas transduction of cells with an active form of IκB kinase-β (IKKβ) led to decreased levels of H60a. The regulation probably occurred at the transcriptional level, because NF-κB pathway inhibition led to increased H60a transcripts and promoter activity. Moreover, treatment of tumour cells with slz enhanced their killing by NK cells in vitro, suggesting that NF-κB inhibition can lead to tumour cell rejection. Indeed, when we blocked the NF-κB pathway specifically in tumour cells, there was decreased tumour growth in wild-type but not immune-deficient mice. Our results suggest that reagents that can block NF-κB activity specifically in the tumour and not the host immune cells would be efficacious for tumour therapy.

The nuclear factor-κB pathway down-regulates expression of the NKG2D ligand H60a in vitro: implications for use of nuclear factor-κB inhibitors in cancer therapy

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The transporter-opsin-G protein-coupled receptor (TOG) superfamily.

The nuclear factor-κB pathway down-regulates expression of the NKG2D ligand H60a in vitro: implications for use of nuclear factor-κB inhibitors in cancer therapy