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Balancing Specificity and Promiscuity in Enzyme Evolution: Multidimensional Activity Transitions in the Alkaline Phosphatase Superfamily
Highly proficient, promiscuous enzymes can be springboards for functional evolution, able to avoid loss of function during adaptation by their capacity to promote multiple reactions. We employ systematic comparative study of structure, sequence and substrate specificity to track the evolution of specificity and reactivity between promiscuous members of clades of the alkaline phosphatase (AP) superfamily. Construction of a phylogenetic tree of protein sequences maps out the likely transition zone between arylsulfatases (ASs) and phosphonate monoester hydrolases (PMHs). Kinetic analysis shows that all enzymes characterized have four chemically distinct phospho- and sulfoesterase activities, with rate accelerations ranging from 1011-1017-fold for their primary and 109-1012-fold for their promiscuous reactions, suggesting that catalytic promiscuity is widespread in the AP-superfamily. This functional characterization and crystallography reveal a novel class of ASs that is so similar in sequence to known PMHs that it had not been recognized as having diverged in function. Based on analysis of snapshots of catalytic promiscuity ‘in transition’ we develop possible models that would allow functional evolution and determine scenarios for trade-off between multiple activities. For the new ASs we observe largely invariant substrate specificity that would facilitate the transition from ASs to PMHs via trade-off-free molecular exaptation, i.e. evolution without initial loss of primary activity and specificity toward the original substrate. This ability to bypass low activity generalists provides a molecular solution to avoid adaptive conflict.BBSR
Evaluación del daño estructural de manos mediante RM en pacientes con artritis reumatoidea temprana, sin evidencia de erosiones radiográficas Assessment of structural damage of hands by MRI in patients with early rheumatoid arthritis, without evidence of erosions in radiography
Introducción: La Artritis Reumatoidea (AR) se caracteriza por la inflamación crónica de las articulaciones, lo que lleva a la destrucción del cartÃlago articular y del hueso. Aproximadamente el 75% de los pacientes con AR desarrolla erosiones articulares dentro de los dos primeros años de comienzo de los sÃntomas. La presencia de erosiones tempranas expresa enfermedad más agresiva y se asocia a un pronóstico más desfavorable. Se ha demostrado que el daño erosivo puede observarse en resonancia magnética (RM) aun antes de los 6 meses luego de iniciada la enfermedad, siendo esta técnica de mayor sensibilidad que la radiologÃa convencional. La evaluación por RM utilizando el score de Outcome Measures in Rheumatology Clinical Trials (OMERACT) / Rheumatoid Arthritis Magnetic Resonance Imaging Score (RAMRIS) permite realizar una valoración semicuantitativa del edema óseo, la sinovitis y las erosiones. Objetivo: Evaluar las caracterÃsticas del daño estructural por RM en pacientes con AR temprana (menos de un año de evolución) que no presentaron erosiones en radiografÃas de manos. Materiales y métodos: Se seleccionaron 10 pacientes con AR según criterios ACR 1987, que presentaban score radiológico de Sharp / van der Heijde igual a 0 (cero) para erosiones. A ellos se les realizó RM de ambas manos. Se utilizó el score de Sharp / van der Heijde para evaluar el pinzamiento articular y el score de OMERACT-RAMRIS para cuantificar las lesiones articulares detectadas por RM. Se comparó el score final obtenido por ambos métodos. Resultados: Se incluyeron 10 pacientes (9 mujeres y 1 varón) con score radiológico de Sharp / van der Heijde igual a cero para erosiones. La edad media fue de 45,8 años (rango 25 - 71). El tiempo medio de evolución de la AR a la obtención de las imágenes fue de 3,6 meses (rango 1 - 8). El score medio de pinzamiento radiológico fue de 52 (rango 36 - 83). El score medio OMERACT-RAMRIS fue de 24 (rango 4-55); todos los pacientes presentaron sinovitis y 7 (70 %), edema óseo. Apesar de no observarse erosiones en la radiografÃa, 7 pacientes (70 %) las mostraron en RM. La erosión representó el 26,25% del score total de RM. Conclusión: Tradicionalmente, el daño estructural de la AR se mide utilizando diferentes métodos de score radiológicos. Dado que la detección precoz de erosiones predice una enfermedad más agresiva, la RM deberÃa ser considerada en pacientes con AR temprana para la evaluación del pronóstico. Sin embargo, es necesario evaluar a un mayor número de pacientes para certificar esta observación.<br>Introduction: Rheumatoid Arthritis (RA) is characterized by chronic inflammation of the joints, leading to destruction of articular cartilage and bone. Approximately 75% of RA patients develop joint erosions within the first two years of onset of symptoms. The presence of early erosions reveals more aggressive disease and is associated with an unfavorable prognosis. It has been shown that erosion damage can be seen on magnetic resonance imaging (MRI) even before 6 months of the disease onset. This technique appears to be more sensitive than conventional radiology. MRI evaluation using the score of Outcome Measures in Rheumatology Clinical Trials (OMERACT) / Rheumatoid Arthritis Magnetic Resonance Imaging Score (RAMRIS) allows semiquantitative assessment of bone edema, synovitis and erosions. Objective: To evaluate the characteristics of structural damage by MRI in patients with early RA (less than one year of progression), with no erosions of hands on the X-ray. Materials and methods: We selected 10 patients with RA according to the ACR criteria 1987, whose score showed radiographic Sharp / van der Heijde equal to 0 (zero) for erosions. They underwent MRI of both hands. The Sharp / van der Heijde method was used to assess articular impingement, and the OMERACT-RAMRIS score to quantify joint lesions detected by MRI. The final scores obtained by both methods were compared. Results: Ten patients (9 females and 1 male) with radiographic score Sharp / van der Heijde zero for erosion were included. Mean age was 45.8 years (range 25-71). When the MRI was performed, the mean time of RA progression was 3.6 months (range 1 to 8). The average score was 52 radiological clamping (range 36 to 83). The OMERACT-RAMRIS half score was 24 (range 4- 55); all patients had synovitis, and 7 (70%) had bone edema. Although no erosions have been seen on radiographs, in 7 patients (70%) erosions were seen on the MRI. Erosions accounted for 26.25% of the total MRI score. Conclusion: Traditionally, the RA-related structural damage has been measured using different radiological score methods. Since early detection of erosions predicts a more aggressive disease, MRI should be considered in patients with early RA to evaluate their prognosis. However, a larger number of patients should be analyzed to confirm this observation
TRANSVAC workshop on standardisation and harmonisation of analytical platforms for HIV, TB and malaria vaccines: ‘How can big data help?’
Immunogenetics and cellular immunology of bacterial infectious disease