Cardiolipin (CL) is a unique phospholipid which is present throughout the eukaryotic kingdom and is localized in mitochondrial membranes. Saccharomyces cerevisiae cells containing a disruption of CRD1, the structural gene encoding CL synthase, have no CL in mitochondrial membranes. To elucidate the physiological role of CL, we compared mitochondrial functions in the crd1⌬ mutant and isogenic wild type. The crd1⌬ mutant loses viability at elevated temperature, and prolonged culture at 37°C leads to loss of the mitochondrial genome. Mutant membranes have increased phosphatidylglycerol (PG) when grown in a nonfermentable carbon source but have almost no detectable PG in medium containing glucose. In glucose-grown cells, maximum respiratory rate, ATPase and cytochrome oxidase activities, and protein import are deficient in the mutant. The ADP/ATP carrier is defective even during growth in a nonfermentable carbon source. The mitochondrial membrane potential is decreased in mutant cells. The decrease is more pronounced in glucose-grown cells, which lack PG, but is also apparent in membranes containing PG (i.e. in nonfermentable carbon sources). We propose that CL is required for maintaining the mitochondrial membrane potential and that reduced membrane potential in the absence of CL leads to defects in protein import and other mitochondrial functions.1 is a structurally unique phospholipid that carries four acyl groups and two negative charges. It is thus highly hydrophobic and acidic. The biosynthesis of CL occurs in three enzymatic steps (1-3). Phosphatidylglycerolphosphate (PGP) synthase catalyzes the formation of PGP from phosphatidyl-CMP (CDP-diacylglycerol; CDP-DG) and glycerol 3-phosphate. PGP is then dephosphorylated to phosphatidylglycerol (PG) by PGP phosphatase. Eukaryotes and bacteria utilize different reactions to convert PG to CL. In prokaryotes, CL synthase catalyzes a phosphatidyl transfer between two PG molecules (4). This is a near-equilibrium (transesterification) reaction that is mainly controlled by substrate availability. In contrast, eukaryotic CL synthase catalyzes a phosphatidyl transfer from CDP-DG to PG (5-7). This is an irreversible reaction that involves cleavage of a high energy anhydride bond. This reaction can take place in the presence of low substrate concentration and is mainly regulated by CL synthase activity. The differences in these reactions probably reflect different functions of PG and CL in prokaryotes and mitochondria.In Escherichia coli, the enzymes that catalyze the synthesis of CL have been characterized biochemically, and the genes encoding these enzymes have been cloned. Although disruption of the cls gene (encoding CL synthase) is not lethal, bacterial strains bearing a null allele of pgsA (encoding PGP synthase) are inviable (8, 9). Interestingly, bacterial cls null mutants do synthesize CL, presumably by another enzyme. These experiments suggest that the anionic phospholipids PG and/or CL are essential for bacterial viability.
The catalytic properties of RNA and its well known role in gene expression and regulation are the consequence of its unique solution structures. Identification of the structural determinants of ligand recognition by RNA molecules is of fundamental importance for understanding the biological functions of RNA, as well as for the rational design of RNA Sequences with specific catalytic activities. Towards this latter end, Szostak et al. used in vitro selection techniques to isolate RNA sequences ('aptamers') containing a high-affinity binding site for ATP, the universal currency of cellular energy, and then used this motif to engineer ribozymes with polynucleotide kinase activity. Here we present the solution structure, as determined by multidimensional NMR spectroscopy and molecular dynamics calculations, of both uniformly and specifically 13C-, 15N-labelled 40-mer RNA containing the ATP-binding motif complexed with AMP. The aptamer adopts an L-shaped structure with two nearly orthogonal stems, each capped proximally by a G x G mismatch pair, binding the AMP ligand at their junction in a GNRA-like motif.
Nucleic acid aptamers have minimal immunogenicity, high chemical synthesis production, low cost and high chemical stability when compared with antibodies. However, the susceptibility to nuclease degradation, rapid excretion through renal filtration and insufficient binding affinity hindered their development as drug candidates for therapeutic applications. In this review, we will discuss methods to conquer these challenges and highlight recent developments of chemical modifications and technological advances that may enable early aptamers to be translated into clinical therapeutics.
Novel features of RNA structure, recognition and discrimination have been recently elucidated through the solution structural characterization of RNA aptamers that bind cofactors, aminoglycoside antibiotics, amino acids and peptides with high affinity and specificity. This review presents the solution structures of RNA aptamer complexes with adenosine monophosphate, flavin mononucleotide, arginine/citrulline and tobramycin together with an example of hydrogen exchange measurements of the base-pair kinetics for the AMP-RNA aptamer complex. A comparative analysis of the structures of these RNA aptamer complexes yields the principles, patterns and diversity associated with RNA architecture, molecular recognition and adaptive binding associated with complex formation.
SummaryCardiolipin is a unique dimeric phospholipid, which is present throughout the eukaryotic kingdom and is specifically localized in mitochondrial membranes. It is widely believed that mitochondria possess an essential requirement for this phospholipid. To determine whether cardiolipin is essential for yeast growth, we generated a cardiolipin synthase null mutant by disrupting the CLS1 gene (open reading frame YDL142c on chromosome IV) of Saccharomyces cerevisiae. Biochemical analysis of the mutant indicated that it had no cardiolipin synthase activity and no cardiolipin in its membranes. The enzyme phosphatidylglycerolphosphate synthase, which catalyses the committed step of the cardiolipin pathway, remained unaffected in the null mutant. Haploid cells containing the null allele are viable in media containing glucose, galactose or glycerol/ethanol as the sole carbon source, although growth in galactose or glycerol/ethanol is somewhat reduced in the mutant compared with the wild type. These results indicate that cardiolipin is not essential for the growth of S. cerevisiae in fermentable or nonfermentable carbon sources.
Antibody–drug conjugates (ADCs) comprised of a desirable monoclonal antibody, an active cytotoxic drug and an appropriate linker are considered to be an innovative therapeutic approach for targeted treatment of various types of tumors and cancers, enhancing the therapeutic parameter of the cytotoxic drug and reducing the possibility of systemic cytotoxicity. An appropriate linker between the antibody and the cytotoxic drug provides a specific bridge, and thus helps the antibody to selectively deliver the cytotoxic drug to tumor cells and accurately releases the cytotoxic drug at tumor sites. In addition to conjugation, the linkers maintain ADCs’ stability during the preparation and storage stages of the ADCs and during the systemic circulation period. The design of linkers for ADCs is a challenge in terms of extracellular stability and intracellular release, and intracellular circumstances, such as the acid environment, the reducing environment and cathepsin, are considered as the catalysts to activate the triggers for initiating the cleavage of ADCs. This review discusses the linkers used in the clinical and marketing stages for ADCs and details the fracture modes of the linkers for the further development of ADCs.
Perovskite quantum dots are emerging as attractive materials for photonic and optoelectronic applications. Patterning is an important step to incorporate them into display, anti‐counterfeiting, and optical chip applications. In this work, an in situ inkjet printing strategy is demonstrated for fabricating perovskite quantum dots patterns by printing perovskite precursor solutions onto a polymeric layer. Importantly, this strategy can achieve bright photoluminescence with a quantum yield up to 80% and shows broad applicability to a variety of perovskites and polymers. Moreover, the as‐fabricated perovskite quantum dots patterns are composed of a microdisks array on the surface of polymeric layer. The size of these microdisks can be varied by adjusting the printing temperature. To demonstrate the potential use in display and advanced anti‐counterfeiting applications, color pixel patterns and 2D code pattern are fabricated by varying the precursor solutions. The combination of superior photoluminescence properties, simple process, and low cost makes the in situ inkjet printing strategy very promising for patterning perovskite quantum dots toward photonic integrations.
Size-controllable amine-functionalized graphene quantum dots (GQDs) are prepared by an eco-friendly method with graphene oxide sheets, ammonia and hydrogen peroxide as starting materials. Using a Sephadex G-25 gel column for fine separation, for the first time we obtain GQDs with either single or double layers. By atomic force microscopy characterization, we confirm that hydrogen peroxide and ammonia play a synergistic role on graphene oxide (GO), in which the former cuts the GO into small pieces and the latter passivates the active surface to give amine-modified GQDs. Due to the low cytotoxicity and excellent biocompatibility of the obtained amine-functionalized GQDs, besides the multiwavelength imaging properties of GQDs, for the first time we find that this kind of GQD exhibits good antimycoplasma properties. Given the superior antimycoplasma effect of the GQDs and their eco-friendly mass production with low cost, these new GQDs may offer opportunities for the development of new antimycoplasma agents, thus extending their widespread application in biomedicine.
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