Quantum control of a cat qubit with bit-flip times exceeding ten seconds.

Quantum bits (qubits) are prone to several types of error as the result of uncontrolled interactions with their environment. Common strategies to correct these errors are based on architectures of qubits involving daunting hardware overheads1. One possible solution is to build qubits that are inherently protected against certain types of error, so the overhead required to correct the remaining errors is greatly reduced2-7. However, this strategy relies on one condition: any quantum manipulations of the qubit must not break the protection that has been so carefully engineered5,8. A type of qubit known as a cat qubit is encoded in the manifold of metastable states of a quantum dynamical system, and thereby acquires continuous and autonomous protection against bit-flips. Here, in a superconducting-circuit experiment, we implemented a cat qubit with bit-flip times exceeding 10 s. This is an improvement of four orders of magnitude over previously published cat-qubit implementations. We prepared and imaged quantum superposition states, and measured phase-flip times greater than 490 ns. Most importantly, we controlled the phase of these quantum superpositions without breaking the bit-flip protection. This experiment demonstrates the compatibility of quantum control and inherent bit-flip protection at an unprecedented level, showing the viability of these dynamical qubits for future quantum technologies.

New opto-electro-mechanical sensor for two-dimensions dosimetry based on radiochromic films.

This work presents the validation of a new Opto‒Electro-Mechanical (MOEM) system consisting of a matrix of photodetectors for two-dimensional dosimetry evaluation with radiochromic films. The proposed system is based on a 5 × 10 matrix of photodetectors controlled by both in-house electronic circuit and graphical user interface, which enables optical measurements directly. We present the first tests performed in an X-ray machine and 137Cs source with that array by using Gafchromic EBT3 films. We obtained similar results than with a standard method (e.g. flat-bed scanner). Results were compared with Monte Carlo simulations and very good agreement was found. Results show the feasibility of using this system for dose evaluations. To the best of our knowledge, this is the first MOEM sensor for radiotherapy. Further developments are ongoing to create an advanced 16 × 16 LDRs system covering 1.6 cm × 1.6 cm with a 1 mm of spatial resolution. We point to develop a portable dosimetry tool delivering dose maps in real time to improve the clinical application of radiochromic films.

Perception of Protective Stabilization by Pediatric Dentists: A Qualitative Study.

INTRODUCTION: Pediatric dentists sometimes have to care for children who refuse to cooperate with the oral examination or dental treatment. Behavior management strategies are used, such as "tell-show-do," distraction, and positive reinforcement. Anxiety management can also be performed by the use of conscious sedation (oral premedication, nitrous oxide/oxygen inhalation). Unfortunately, these techniques are sometimes insufficient for providing oral care, and protective stabilization may be an option in some situations. Little is known on the impact of physical restraint and how practitioners feel about it. The objective of this study was to evaluate the perception of dentists using protective stabilization for dental care in children. METHODS: Semistructured qualitative interviews on the perception of pediatric dentists concerning protective stabilization were conducted in the pediatric dentistry department of the University Hospital of Toulouse, France. A thematic analysis of interview transcripts was provided via NVivo software. RESULTS: This analysis highlighted 3 main themes. First, the perceptions of dentists concerning protective stabilization showed that this procedure has a major psychological impact and led to a feeling of professional failure. Second, the reasons for which the child was stabilized were described; these concerned the child (behavior, age, number of treatments) and the environment (the parents and the medical team). Finally, we detailed how dentists manage the effects of using of protective stabilization. CONCLUSION: Dental surgeons must balance their requirement to make concrete decisions regarding the provision of care with their personal convictions about protective stabilization. This study also shows the need for specific training on this subject, as well as the desire of certain dentists that public authorities implement legislation on this matter. KNOWLEDGE TRANSFER STATEMENT: The findings of this study will improve the management of young patients by identifying situations where protective stabilization may be useful (age of the child, diagnosis, protection of the child or the medical team), while showing its psychological impact on practitioners. Finally, this work provides a basis for decision makers to propose a framework for the use of physical restraint.

Cadmium bioaccumulation and gastric bioaccessibility in cacao: A field study in areas impacted by oil activities in Ecuador.

Cacao from South America is especially used to produce premium quality chocolate. Although the European Food Safety Authority has not established a limit for cadmium (Cd) in chocolate raw material, recent studies demonstrate that Cd concentrations in cacao beans can reach levels higher than the legal limits for dark chocolate (0.8 mg kg-1, effective January 1st, 2019). Despite the fact that the presence of Cd in agricultural soils is related to contamination by fertilizers, other potential sources must be considered in Ecuador. This field study was conducted to investigate Cd content in soils and cacao cultivated on Ecuadorian farms in areas impacted by oil activities. Soils, cacao leaves, and pod husks were collected from 31 farms in the northern Amazon and Pacific coastal regions exposed to oil production and refining and compared to two control areas. Human gastric bioaccessibility was determined in raw cacao beans and cacao liquor samples in order to assess potential health risks involved. Our results show that topsoils (0-20 cm) have higher Cd concentrations than deeper layers, exceeding the Ecuadorian legislation limit in 39% of the sampling sites. Cacao leaves accumulate more Cd than pod husks or beans but, nevertheless, 50% of the sampled beans have Cd contents above 0.8 mg kg-1. Root-to-cacao transfer seems to be the main pathway of Cd uptake, which is not only regulated by physico-chemical soil properties but also agricultural practices. Additionally, natural Cd enrichment by volcanic inputs must not be neglected. Finally, Cd in cacao trees cannot be considered as a tracer of oil activities. Assuming that total Cd content and its bioaccessible fraction (up to 90%) in cacao beans and liquor is directly linked to those in chocolate, the health risk associated with Cd exposure varies from low to moderate.

Three years of antibiotic consumption evaluation in French nursing homes.

OBJECTIVES: We had for aim to assess antibiotic consumption and to better understand their use in nursing homes so as to target messages on relevant practice procedures sent to prescribers. DESIGN: The MedQual network asked nursing homes with in-house pharmacies to participate in a retrospective collection of yearly antibiotic consumption data with an Excel(®) spread sheet according to the Health Ministry recommendations. RESULTS: Fifty-two nursing homes participated in 2011, 2012, and 74 in 2013, accounting for 10% of the Pays de la Loire region's nursing homes and 15% of beds. The medians of total antibiotic consumption in daily-defined dose for 1000 patient-days were respectively 39 (32.4-49.0), 39.3 (34.4-52.9), and 44.8 (33.6-55.4). There was no significant difference between 2011 and 2013. Penicillins (J01C) were the most commonly used class with a median of 25.7 [IQ 18.8; 33.8] in 2011 and 30.4 [IQ 23.6; 41.3] in 2013. Quinolones (J01M) were the second most commonly used class with a median of 4.6 [IQ 2.9; 5.9] in 2011 and 3.8 [IQ 2.3; 6.5] in 2013, followed by the other beta-lactams (J01D) with a median of 2.5 [IQ 1.7; 4.5] in 2011 and 2,8 [IQ 1.7; 3.8] in 2013. CONCLUSION: The monitoring of antibiotic consumption in nursing homes in the Pays de la Loire Region since 2011 has allowed identifying inappropriate use and helped improve practices. No increase of overall consumption was observed in nursing homes but the distribution according to antibiotic class changed. The current objective is to extend this monitoring and to send personalized messages to prescribers.

Epidemiology of third-generation cephalosporin-resistant community-acquired Enterobacteria isolated from elderly patients.

AIMS: This survey was made to study the epidemiology of multiresistant bacteria (MRB) in the French community, among elderly patients 65 years of age or more, carrying third-generation cephalosporin-resistant (3GC-resistant) Enterobacteriaceae, and the co-resistance of prescribed antibiotics. METHODS: The data was collected in 2009 in the West of France by MedQual, a network of 174 private laboratories. RESULTS: Two thousand one hundred and sixty strains of the 88,255 identified Enterobacteria strains were 3GC-resistant (2.4%) and 945 of these strains (41.8%) were isolated from elderly patients 65 years of age or more. Escherichia coli was the predominant 3GC-resistant strain (72.7%). 51.4% of the 945 patients in whom a 3GC-resistant strain was isolated produced an extended-spectrum ß-lactamase (ESBL). The main risk factors for infection with the 3GC-resistant strain were hospitalization and antibiotic treatment in the previous year (58.2 and 86.9%, respectively). Hospitalization during the previous year was more frequent among elderly patients who lived at home compared with those who lived in nursing homes (P<0.05). The production of ESBL, among the 945 patients who carried the 3GC-resistant strains, was similar among patients who lived at home compared with those who lived in nursing homes (51.4% versus 49.7%). CONCLUSION: Microbiologists should warn family physicians about MRB isolates with a specific antimicrobial resistance pattern (3GC-resistant, fluoroquinolone-resistant, etc.) to prescribe more effective medications.

A national network of infectious diseases experts.

OBJECTIVES: The aim of this study was to consider the implementation of a network of infectious diseases (ID) experts to optimize the antibiotic prescriptions of community and hospital practitioners. METHODS: An observational prospective study was conducted among ID experts in the Pays-de-la-Loire Region to evaluate the number of calls and to determine the practitioner's reasons for soliciting ID expertise. For each phone consultation, four criteria were recorded during 5 days: origin of the call (internal/external), kind of question (diagnostic/therapeutic) time spent for the advice provided, type of advice. RESULTS: A total of 386 phone consultations for 20 infectious disease specialists were recorded during the study period (5 days); 81% were internal to the hospital, 7.7% from another hospital, and 11.3% from private practice, 56.3% of the questions concerned a therapeutic strategy, 21% a diagnostic advice, and 22.6% concerned both diagnosis and therapy. Two third of the questions were answered within 10minutes. In 68.7% of cases, the ID specialist answered immediately, 19.8% of calls required following-up the patient, 6% led to refer the patient to an ID consultation, and 5.5% to hospitalization. CONCLUSION: The survey results stress the important need for such ID expertise, both in hospitals and in ambulatory medicine. Collaboration of ID specialists in a regional network would allow an easy and permanent access to antibiotic therapy advice for prescribers. This network would improve the quality and safety of care.

The effect of safinamide, a novel drug for Parkinson's disease, on pressor response to oral tyramine: a randomized, double-blind, clinical trial.

This randomized, double-blind, placebo-, comparator (selegiline 10 mg/day)-, and positive (phenelzine 30 mg/day)-controlled study investigated the pressor response to oral tyramine under fasting conditions after the administration of safinamide at therapeutic (100 mg/day) and supratherapeutic (350 mg/day) dosing regimens in healthy volunteers for the purpose of assessing the need for dietary restrictions. Pressor response was characterized by Tyr30, defined as the tyramine dose that triggers a sustained increase in systolic blood pressure (SBP) of ≥30 mm Hg as compared with baseline SBP. The primary end point was the tyramine sensitivity factor (TSF), defined as the ratio of Tyr30 at screening to Tyr30 under treatment. Safinamide induced a mild increase in TSF; however, the effect at each of the doses was numerically lower than those of the comparators (geometric mean TSFs: placebo, 1.52; safinamide 100 mg, 2.15; safinamide 350 mg, 2.74; selegiline, 3.12; phenelzine, 9.98). This study confirms that safinamide is a highly selective monoamine oxidase-B inhibitor, even at supratherapeutic doses, and suggests that it can be administered without tyramine-related dietary restrictions.

[Retrospective, descriptive, observational study of treatment of multiple actinic keratoses with topical methyl aminolevulinate and red light: results in clinical practice and correlation with fluorescence imaging]. / Estudio retrospectivo, descriptivo y observacional del tratamiento de queratosis actínicas múltiples con metilaminolevulinato tópico y luz roja: resultados en la práctica clínica y correlación con la imagen de fluorescencia.

BACKGROUND: Actinic keratosis (AK) is one of the most common skin diseases seen in clinical practice. In the last 5 years, several studies assessing the efficacy of photodynamic therapy in the treatment of multiple AKs have been published. OBJECTIVE: We aimed to assess the clinical outcomes of photodynamic therapy in patients with multiple AKs and the correlation of those outcomes with fluorescence imaging. MATERIAL AND METHODS: In this retrospective, descriptive, observational study of 57 patients treated in our hospital with photodynamic therapy for multiple AKs, we recorded age, sex, and lesion site (face, scalp, and dorsum of the hands). All patients were treated in the same way: methyl aminolevulinic acid (Metvix) was applied for 3 hours and the skin then irradiated with red light at 630 nm, 37 J/cm(2), for 7.5 minutes (Aktilite). The response, remission duration, tolerance, number of sessions, and fluorescence images were recorded by site. The chi(2) test was used to assess between-site differences and the correlation between fluorescence imaging and clinical response. RESULTS: The greatest improvements were obtained for facial lesions; these required fewer sessions and remission lasted longer than lesions at other sites. The treatment was best tolerated on the dorsum of the hands. The fluorescence area and the reduction in intensity on applying treatment were found to be strongly and significantly correlated with the extent of clinical response. CONCLUSIONS: Overall, the outcomes of treatment of multiple AKs with photodynamic therapy are better for the face than for the scalp and dorsum of the hands. Fluorescence imaging may be an effective tool for predicting response to treatment.

Estudio retrospectivo, descriptivo y observacional del tratamiento de queratosis actínicas múltiples con metilaminolevulinato tópico y luz roja: resultados en la práctica clínica y correlación con la imagen de fluorescencia / Retrospective, descriptive, observational study of treatment of multiple actinic keratoses with topical methyl aminolevulinate and red light: results in clinical practice and correlation with fluorescence imaging

Introducción. Las queratosis actínicas (QA) son una de las patologías cutáneas más frecuentes en la práctica clínica. En los últimos 5 años se han publicado varios estudios que evaluaban la eficacia de la terapia fotodinámica (TFD) en el tratamiento de múltiples QA. Objetivo. Evaluar los resultados de la TFD de múltiples QA por localizaciones y su correlación con la imagen de fluorescencia. Material y métodos. Realizamos un estudio retrospectivo, descriptivo y observacional de los pacientes tratados por múltiples QA con TFD en nuestro hospital. Se describe la edad, el sexo y la localización de las lesiones (cara, cuero cabelludo y dorso de las manos) de los 57 pacientes. Se trató a todos los pacientes usando los mismos parámetros: ácido metilaminolevulínico (MAL, Metvix®) ocluido tres horas e irradiación con luz roja de 630 nm, 37 J/cm2, 7,5 minutos (Aktilite®). Se describe la respuesta, período de remisión, tolerancia, número de sesiones y la fluorescencia según localizaciones. Con la prueba Chi-cuadrado se evalúan las diferencias entre localizaciones y la correlación de la imagen de fluorescencia con la respuesta clínica. Resultados. En la cara se obtiene mayor grado de mejoría, se requieren menor número de sesiones y mayores períodos de remisión que en el resto de las localizaciones. El dorso de las manos es la zona mejor tolerada. Existe una correlación alta y significativa entre el área de fluorescencia y su disminución al aplicar el tratamiento, con el grado de respuesta clínica. Conclusiones. Los resultados en el tratamiento de múltiples QA con TFD son mejores, globalmente, en la cara que en el cuero cabelludo y en el dorso de manos. El diagnóstico de fluorescencia puede ser una herramienta eficaz para predecir la respuesta al tratamiento (AU)

Background. Actinic keratosis (AK) is one of the most common skin diseases seen in clinical practice. In the last 5 years, several studies assessing the efficacy of photodynamic therapy in the treatment of multiple AKs have been published. Objective. We aimed to assess the clinical outcomes of photodynamic therapy in patients with multiple AKs and the correlation of those outcomes with fluorescence imaging. Material and methods. In this retrospective, descriptive, observational study of 57 patients treated in our hospital with photodynamic therapy for multiple AKs, we recorded age, sex, and lesion site (face, scalp, and dorsum of the hands). All patients were treated in the same way: methyl aminolevulinic acid (Metvix®) was applied for 3 hours and the skin then irradiated with red light at630 nm, 37 J/cm2, for 7.5 minutes (Aktilite®). The response, remission duration, tolerance, number of sessions, and fluorescence images were recorded by site. The X2 test was used to assess between-site differences and the correlation between fluorescence imaging and clinical response. Results. The greatest improvements were obtained for facial lesions; these required fewer sessions and remission lasted longer than lesions at other sites. The treatment was best tolerated on the dorsum of the hands. The fluorescence area and the reduction in intensity on applying treatment were found to be strongly and significantly correlated with the extent of clinical response. Conclusions. Overall, the outcomes of treatment of multiple AKs with photodynamic therapy are better for the face than for the scalp and dorsum of the hands. Fluorescence imaging may be an effective tool for predicting response to treatment (AU)

Selectividad de la fototermólisis en el tratamiento de las manchas en vino de Oporto mediante múltiples pulsos de láser de colorante pulsado / Selectivity of photothermolysis in the treatment of port wine stains using multiple pulses with a pulsed dye laser

Introducción. En un 25-50 % de los pacientes con manchas en vino de Oporto tratadas con láser decolorante pulsado (incluso con múltiples sesiones) obtenemos un resultado parcial y frecuentemente insatisfactorio para el paciente. Se han propuesto varios factores que explicarían esta resistencia al tratamiento, como la presencia de vasos profundos, de pequeño calibre o muy gruesos, a los que un solo pulso de láser no logra coagular. Existen modelos matemáticos que sugieren que los multipulsos serían eficaces para coagular estos vasos sin perder la selectividad de la fototermólisis, ya que permiten administrar más energía sobre las estructuras diana, sin lesionar el tejido circundante. El objetivo de este estudio es evaluar la eficacia y la selectividad de la fototermólisis al usar multipulsos. Métodos. Se seleccionaron 12 pacientes con manchas en vino de Oporto. Se trataron varias zonas de cada lesión con láser de colorante pulsado (V-beam 595 nm, Candela®) y distintos parámetros. Inmediatamente después se biopsiaron las zonas tratadas. Resultados. El riesgo de sobre dosificar fue mayor con tamaños del haz pequeños, pulsos largos, intervalo breve entre pulsos y fluencias elevadas. El daño térmico fue menor con tamaños del haz de 10 mm, pulsos cortos, intervalo de 1 minuto entre los pulsos y fluencias bajas. En casos seleccionados, los multipulsos eran eficaces y selectivos, ahí donde el pulso único no lograba coagular los vasos. Conclusiones. Nuestros resultados ponen de manifiesto las enormes posibilidades que los multipulsos ofrecen para el tratamiento de las lesiones vasculares refractarias. Asimismo, definimos los parámetros que intervienen en este complejo proceso termodinámico de interacción del láser con el tejido cutáneo, se señalan cuáles son más seguros y apuntamos su utilidad con otros láseres y patologías cutáneas (AU)

Background. In 25 % to 50 % of patients with port wine stains treated with pulsed dye laser (even in multiple sessions), only a partial improvement is obtained that is often unsatisfactory for the patient. Various factors have been proposed to explain the resistance to treatment, such as the presence of deep, small-caliber, or very thick vessels that cannot be coagulated with a single laser pulse. Certain mathematical models suggest that multiple pulses would be effective in coagulating those vessels without losing the selectivity of photothermolysis, since more energy could be delivered to the target structures without damaging the surrounding tissue. The aim of this study was to assess the efficacy and selectivity of photothermolysis with multiple laser pulses. Methods. Twelve patients with port wine stains were included in the study. Various areas of each lesion were treated with pulsed dye laser (Candela V-beam, 595 nm) using different parameters. Immediately after wards ,the treated areas were biopsied. Results. The risk of exceeding an appropriate dose was greater with small spot size, long pulse duration, short intervals between pulses, and high fluences. Heat damage was less with spots of 10 mm, short pulses, intervals of 1 minute between pulses, and low fluences. In selected cases, multiple pulses were effective and selective where single pulses did not successfully coagulate the vessels. Conclusions. Our results indicate the enormous possibilities of multiple laser pulses for the treatment of refractory vascular lesions. In addition, we have addressed the variables defining the complex thermodynamic interaction between the laser and the cutaneous tissue and indicated the safest parameters. We discuss the possible usefulness of this approach with other lasers and skin diseases (AU)

[Selectivity of photothermolysis in the treatment of port wine stains using multiple pulses with a pulsed dye laser]. / Selectividad de la fototermólisis en el tratamiento de las manchas en vino de Oporto mediante múltiples pulsos de láser de colorante pulsado.

BACKGROUND: In 25 % to 50 % of patients with port wine stains treated with pulsed dye laser (even in multiple sessions), only a partial improvement is obtained that is often unsatisfactory for the patient. Various factors have been proposed to explain the resistance to treatment, such as the presence of deep, small-caliber, or very thick vessels that cannot be coagulated with a single laser pulse. Certain mathematical models suggest that multiple pulses would be effective in coagulating those vessels without losing the selectivity of photothermolysis, since more energy could be delivered to the target structures without damaging the surrounding tissue. The aim of this study was to assess the efficacy and selectivity of photothermolysis with multiple laser pulses. METHODS: Twelve patients with port wine stains were included in the study. Various areas of each lesion were treated with pulsed dye laser (Candela V-beam, 595 nm) using different parameters. Immediately afterwards, the treated areas were biopsied. RESULTS: The risk of exceeding an appropriate dose was greater with small spot size, long pulse duration, short intervals between pulses, and high fluences. Heat damage was less with spots of 10 mm, short pulses, intervals of 1 minute between pulses, and low fluences. In selected cases, multiple pulses were effective and selective where single pulses did not successfully coagulate the vessels. CONCLUSIONS: Our results indicate the enormous possibilities of multiple laser pulses for the treatment of refractory vascular lesions. In addition, we have addressed the variables defining the complex thermodynamic interaction between the laser and the cutaneous tissue and indicated the safest parameters. We discuss the possible usefulness of this approach with other lasers and skin diseases.

Hiperqueratosis palmar simétrica y carcinoma esofágico / Symmetric palmar hyperkeratosis and esophageal carcinoma

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Inhibition of 7,8-diaminopelargonic acid aminotransferase by amiclenomycin and analogues.

Cis and trans stereoisomers of amiclenomycin, a natural L-amino acid antibiotic, have been prepared using unequivocal routes. By using 1H NMR spectroscopy, the configuration of the six-membered ring of natural amiclenomycin was shown to be cis and not trans as originally proposed. Amiclenomycin and some synthetic analogues with the cis configuration irreversibly inactivate DAPA AT (7,8-diaminopelargonic acid aminotransferase), an enzyme involved in biotin biosynthesis, by forming an aromatic PLP (pyridoxal-5'-phosphate)-inhibitor adduct that is tightly bound to the active site. The following kinetic parameters for the inactivation of Escherichia coli DAPA AT by amiclenomycin were derived: K(I)=2 microM and k(inact)=0.4 min(-1). The structure of the aromatic adduct formed upon inactivation was confirmed by UV-visible spectroscopy, X-ray crystal structure determination and MS. Because Mycobacterium tuberculosis DAPA AT is a potential drug target, this enzyme was cloned, overexpressed and purified to homogeneity for biochemical characterization.

Biotin synthase mechanism: an overview.

Biotin synthase, a member of the 'radical SAM' (S-adenosylmethionine) family, converts DTB (dethiobiotin) into biotin. The active form of the Escherichia coli enzyme contains two (Fe-S) centres, a (4Fe-4S) and a (2Fe-2S). The (4Fe-4S)2+/+ mediates the electron transfer required for the reductive cleavage of SAM into methionine and a DOA* (deoxyadenosyl radical). Two DOA*, i.e. two SAM molecules, are consumed to activate the positions 6 and 9 of DTB. A direct transfer of isotope from the labelled substrate into DOAH (deoxyadenosine) has been observed with 2H, although not quantitatively, but not with tritium. The source of the sulphur introduced to form biotin is still under debate. We have shown that the (2Fe-2S)2+ cluster can be reconstituted in the apoenzyme with S2- and Fe2+. When S2- was replaced by [34S2-], [35S2-] or Se2-, biotin containing mostly the sulphur isotopes or selenium was obtained. This leads us to favour the hypothesis that the (2Fe-2S) centre is the sulphur donor, which may explain the absence of turnover of the enzyme. DTBSH (9-mercaptodethiobiotin), which already contains the sulphur atom of biotin, was shown to be an alternative substrate of biotin synthase both in vivo and with a crude extract. When this compound was tested with a well-defined in vitro system, the same turnover of one and similar reaction rates were observed for DTB and DTBSH. We postulate that the same intermediate is formed from both substrates.

Enzymology of carbon-sulfur bond formation.

Mobilization of the sulfur of cysteine as persulfide is the first step of sulfur transfer into thiamin, molydopterin, 4-thiouridine, biotin and lipoic acid, but then the pathways diverge completely. For the first three compounds, one or several proteinic persulfides are involved, ending in the nucleophilic attack of a sulfur, persulfide, sulfide or thiocarboxylate on a carbonyl equivalent. Several proteins have been newly characterized, revealing homologies between the three biosynthetic routes and evolutionary relationships. In the case of biotin, and very probably of lipoic acid, the sulfur is transferred as sulfide into the [Fe-S] center of the enzyme. This [Fe-S] center is the ultimate sulfur donor, which quenches a carbon radical on the substrate. This radical is produced by homolytic cleavage of a C-H bond by a deoxyadenosyl radical arising from the reduction of S-adenosylmethionine.

Biosynthesis of biotin and lipoic acid.

The genetics and mechanistic enzymology of biotin biosynthesis have been the subject of much investigation in the last decade, owing to the interest for biotin production by fermentation, on the one hand, and for the design of inhibitors with potential herbicidal properties, on the other hand. Four enzymes are involved in the synthesis of biotin from its two precursors, alanine and pimeloyl-CoA. They are now well-characterized and the X-ray structures of the first three have been published. 8-Amino-7-oxopelargonic acid synthase is a pyridoxal 5'-phosphate (PLP) enzyme, very similar to other acyl-CoA alpha-oxoamine synthases, and its detailed mechanism has been determined. The origin of its specific substrate, pimeloyl-CoA, however, is not completely established. It could be produced by a modified fatty acid pathway involving a malonyl thioester as the starter. 7,8-Diaminopelargonic acid (DAPA) aminotransferase, although sharing sequence and folding homologies with other transaminases, is unique as it uses S-adenosylmethionine (AdoMet) as the NH2 donor. The mechanism of dethiobiotin synthethase is also now well understood. It catalyzes the formation of the ureido ring via a DAPA carbamate activated with ATP. On the other hand, the mechanism of the last enzyme, biotin synthase, which has long raised a very puzzling problem, is only starting to be unraveled and appears indeed to be very complex. Biotin synthase belongs to the family of AdoMet-dependent enzymes that reductively cleave AdoMet into a deoxyadenosyl radical, and it is responsible for the homolytic cleavage of C-H bonds. A first radical formed on dethiobiotin is trapped by the sulfur donor, which was found to be the iron-sulfur (Fe-S) center contained in the enzyme, and cyclization follows in a second step. Two important features come from these results: (1) a new role for an Fe-S center has been revealed, and (2) biotin synthase is not only a catalyst but also a substrate for the reaction. Lipoate synthase, which catalyzes the formation of two C-S bonds from octanoic acid, has a very high sequence similarity with biotin synthase. Although no in vitro enzymology has been carried out with lipoate synthase, the sequence homology as well as the results of in vivo studies support the conclusion that both enzymes are strongly mechanistically related.