Common to all FASs, PKSs and NRPSs is a remarkable component, the acyl or peptidyl carrier protein (A/PCP). These take the form of small individual proteins in type II systems or discrete folded ...domains in the multi-domain type I systems and are characterized by a fold consisting of three major α-helices and between 60-100 amino acids. This protein is central to these biosynthetic systems and it must bind and transport a wide variety of functionalized ligands as well as mediate numerous protein-protein interactions, all of which contribute to efficient enzyme turnover. This review covers the structural and biochemical characterization of carrier proteins, as well as assessing their interactions with different ligands, and other synthase components. Finally, their role as an emerging tool in biotechnology is discussed.
Q fever is a common cause of febrile illness and community-acquired pneumonia in resource-limited settings. Coxiella burnetii, the causative pathogen, is transmitted among varied host species, but ...the epidemiology of the organism in Africa is poorly understood. We conducted a systematic review of C. burnetii epidemiology in Africa from a "One Health" perspective to synthesize the published data and identify knowledge gaps.
We searched nine databases to identify articles relevant to four key aspects of C. burnetii epidemiology in human and animal populations in Africa: infection prevalence; disease incidence; transmission risk factors; and infection control efforts. We identified 929 unique articles, 100 of which remained after full-text review. Of these, 41 articles describing 51 studies qualified for data extraction. Animal seroprevalence studies revealed infection by C. burnetii (≤13%) among cattle except for studies in Western and Middle Africa (18-55%). Small ruminant seroprevalence ranged from 11-33%. Human seroprevalence was <8% with the exception of studies among children and in Egypt (10-32%). Close contact with camels and rural residence were associated with increased seropositivity among humans. C. burnetii infection has been associated with livestock abortion. In human cohort studies, Q fever accounted for 2-9% of febrile illness hospitalizations and 1-3% of infective endocarditis cases. We found no studies of disease incidence estimates or disease control efforts.
C. burnetii infection is detected in humans and in a wide range of animal species across Africa, but seroprevalence varies widely by species and location. Risk factors underlying this variability are poorly understood as is the role of C. burnetii in livestock abortion. Q fever consistently accounts for a notable proportion of undifferentiated human febrile illness and infective endocarditis in cohort studies, but incidence estimates are lacking. C. burnetii presents a real yet underappreciated threat to human and animal health throughout Africa.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Binding carbohydrates from water is a difficult task, even for the natural carbohydrate-binding proteins known as lectins. The design of synthetic lectin mimics is correspondingly challenging, ...especially if good selectivities are required. In previous work we showed that success is possible, but only for complex polycyclic architectures that require lengthy and low-yielding syntheses; for example, one glucose-selective system was made in 21 steps and only 0.1% overall yield. Here we report the discovery of a simple monocyclic host that matches the earlier designs, but is far more accessible as it is prepared in just five steps and 23% overall yield. The new synthetic lectin binds glucose with excellent selectivity versus other common monosaccharides (for example, ~50:1 versus galactose) and sufficient affinity for glucose sensing at the concentrations found in blood. It also features a built-in signalling system in the form of strong and guest-dependent fluorescence emission. The effectiveness and simplicity of this molecule suggests the potential for development into a new methodology for practical glucose monitoring.
A biomimetic receptor for glucose Tromans, Robert A; Carter, Tom S; Chabanne, Laurent ...
Nature chemistry,
01/2019, Letnik:
11, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Specific molecular recognition is routine for biology, but has proved difficult to achieve in synthetic systems. Carbohydrate substrates are especially challenging, because of their diversity and ...similarity to water, the biological solvent. Here we report a synthetic receptor for glucose, which is biomimetic in both design and capabilities. The core structure is simple and symmetrical, yet provides a cavity which almost perfectly complements the all-equatorial β-pyranoside substrate. The receptor's affinity for glucose, at K
~ 18,000 M
, compares well with natural receptor systems. Selectivities also reach biological levels. Most other saccharides are bound approximately 100 times more weakly, while non-carbohydrate substrates are ignored. Glucose-binding molecules are required for initiatives in diabetes treatment, such as continuous glucose monitoring and glucose-responsive insulin. The performance and tunability of this system augur well for such applications.
Carbohydrate recognition is biologically important but intrinsically challenging, for both nature and host-guest chemists. Saccharides are complex, subtly variable, and camouflaged by hydroxyl groups ...that hinder discrimination between substrate and water. We have developed a rational strategy for the biomimetic recognition of carbohydrates with all-equatorial stereochemistry (β-glucose, analogs, and homologs) and have now applied it to disaccharides such as cellobiose. Our synthetic receptor showed good affinities, not unlike those of some lectins (carbohydrate-binding proteins). Binding was demonstrated by nuclear magnetic resonance, induced circular dichroism, fluorescence spectroscopy, and calorimetry, all methods giving self-consistent results. Selectivity for the target substrates was exceptional; minor changes to disaccharide structure (for instance, cellobiose to lactose) caused almost complete suppression of complex formation.
Brucellosis in low-income and middle-income countries Rubach, Matthew P.; Halliday, Jo E.B.; Cleaveland, Sarah ...
Current opinion in infectious diseases,
2013-October, 2013-Oct, 2013-10-00, 20131001, Letnik:
26, Številka:
5
Journal Article
Recenzirano
Odprti dostop
PURPOSE OF REVIEWHuman brucellosis is a neglected, underrecognized infection of widespread geographic distribution. It causes acute febrile illness and a potentially debilitating chronic infection in ...humans, and livestock infection has substantial socioeconomic impact. This review describes new information regarding the epidemiology of brucellosis in the developing world and advances in diagnosis and treatment.
RECENT FINDINGSThe highest recorded incidence of human brucellosis occurs in the Middle East and Central Asia. Fever etiology studies demonstrate brucellosis as a cause of undifferentiated febrile illness in the developing world. Brucellosis is a rare cause of fever among returning travelers, but is more common among travelers returning from the Middle East and North Africa. Sensitive and specific rapid diagnostic tests appropriate for resource-limited settings have been validated. Randomized controlled trials demonstrate that optimal treatment for human brucellosis consists of doxycycline and an aminoglycoside. Decreasing the burden of human brucellosis requires control of animal brucellosis, but evidence to inform the design of control programs in the developing world is needed.
SUMMARYBrucellosis causes substantial morbidity in human and animal populations. While improvements in diagnostic options for resource-limited settings and stronger evidence for optimal therapy should enhance identification and treatment of human brucellosis, prevention of human disease through control in animals remains paramount.
TA (toxin-antitoxin) systems are widely distributed amongst bacteria and are associated with the formation of antibiotic tolerant (persister) cells that may have involvement in chronic and recurrent ...disease. We show that overexpression of the Burkholderia pseudomallei HicA toxin causes growth arrest and increases the number of persister cells tolerant to ciprofloxacin or ceftazidime. Furthermore, our data show that persistence towards ciprofloxacin or ceftazidime can be differentially modulated depending on the level of induction of HicA expression. Deleting the hicAB locus from B. pseudomallei K96243 significantly reduced persister cell frequencies following exposure to ciprofloxacin, but not ceftazidime. The structure of HicA(H24A) was solved by NMR and forms a dsRBD-like (dsRNA-binding domain-like) fold, composed of a triple-stranded β-sheet, with two helices packed against one face. The surface of the protein is highly positively charged indicative of an RNA-binding protein and His24 and Gly22 were functionality important residues. This is the first study demonstrating a role for the HicAB system in bacterial persistence and the first structure of a HicA protein that has been experimentally characterized.
The Hippo pathway is an important regulator of cell growth, proliferation, and migration. TEAD transcription factors, which lie at the core of the Hippo pathway, are essential for regulation of organ ...growth and wound repair. Dysregulation of TEAD and its regulatory cofactor Yes-associated protein (YAP) have been implicated in numerous human cancers and hyperproliferative pathological processes. Hence, the YAP–TEAD complex is a promising therapeutic target. Here, we use in silico molecular docking using Bristol University Docking Engine to screen a library of more than 8 million druglike molecules for novel disrupters of the YAP–TEAD interaction. We report the identification of a novel compound (CPD3.1) with the ability to disrupt YAP–TEAD protein–protein interaction and inhibit TEAD activity, cell proliferation, and cell migration. The YAP–TEAD complex is a viable drug target, and CPD3.1 is a lead compound for the development of more potent TEAD inhibitors for treating cancer and other hyperproliferative pathologies.
Although catalytic mechanisms in natural enzymes are well understood, achieving the diverse palette of reaction chemistries in re-engineered native proteins has proved challenging. Wholesale ...modification of natural enzymes is potentially compromised by their intrinsic complexity, which often obscures the underlying principles governing biocatalytic efficiency. The maquette approach can circumvent this complexity by combining a robust de novo designed chassis with a design process that avoids atomistic mimicry of natural proteins. Here, we apply this method to the construction of a highly efficient, promiscuous, and thermostable artificial enzyme that catalyzes a diverse array of substrate oxidations coupled to the reduction of H
O
. The maquette exhibits kinetics that match and even surpass those of certain natural peroxidases, retains its activity at elevated temperature and in the presence of organic solvents, and provides a simple platform for interrogating catalytic intermediates common to natural heme-containing enzymes.Catalytic mechanisms of enzymes are well understood, but achieving diverse reaction chemistries in re-engineered proteins can be difficult. Here the authors show a highly efficient and thermostable artificial enzyme that catalyzes a diverse array of substrate oxidations coupled to the reduction of H
O
.
The combination of a pyrenyl tetraamine with an isophthaloyl spacer has led to two new water‐soluble carbohydrate receptors (“synthetic lectins”). Both systems show outstanding affinities for ...derivatives of N‐acetylglucosamine (GlcNAc) in aqueous solution. One receptor binds the methyl glycoside GlcNAc‐β‐OMe with Ka≈20 000 m−1, whereas the other one binds an O‐GlcNAcylated peptide with Ka≈70 000 m−1. These values substantially exceed those usually measured for GlcNAc‐binding lectins. Slow exchange on the NMR timescale enabled structural determinations for several complexes. As expected, the carbohydrate units are sandwiched between the pyrenes, with the alkoxy and NHAc groups emerging at the sides. The high affinity of the GlcNAcyl–peptide complex can be explained by extra‐cavity interactions, raising the possibility of a family of complementary receptors for O‐GlcNAc in different contexts.
Two carbohydrate receptors (see scheme) were prepared directly from a pyrenyl tetraamine and an isophthaloyl derivative. With extended aromatic surfaces linked by polar spacers, they are well suited to binding all‐equatorial monosaccharides, showing especially high affinities for β‐linked N‐acetylglucosamine (GlcNAc).
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