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This article is from BMJ Open , volume 2 . Abstract Objective: Fabry disease (FD) is an X-linked inborn error of glycosphingolipid catabolism caused by deficient lysosomal α-galactosidase A activity. Progressive accumulation of globotriaosylceramide and related glycosphingolipids in vascular endothelial lysosomes of the heart, kidneys and brain is responsible for the main disease manifestations. The aim of our study was to assess short-term and long-term effects of enzyme replacement therapy (ERT) on cardiac mass and function. Design: Retrospective cohort study. Setting: Hospital outpatient clinic. Participants: 40 FD patients (21 men, 19 women) receiving agalsidase β-ERT. Outcome measures: The focus at baseline and follow-up examinations was on structural, functional (Doppler-echocardiography) as well as electrical changes (ECG) and blood pressure. Results: In the Early Group, systolic and diastolic blood pressures significantly decreased. Left-ventricular (LV) also decreased; however, wall thickness and LV mass index showed no further increase. VE as an indicator for diastolic function significantly improved (64±21 vs 75±27 cm/s, p=0.038). There were no significant changes of ECG parameters. There were few relevant changes in the Late Group, albeit systolic blood pressure significantly decreased and QRS duration significantly increased. In conclusion, echocardiographic left-ventricular mass index, interventricular septum thickness, left-ventricular posterior wall, left-ventricular end-diastolic dimension) and diastolic function parameters are valuable for follow-up and guidance of therapy. Conclusions: The primary positive impact of ERT appears to be an early effect after the start of therapy, and early initiation of ERT should be recommended.

This article is from PLoS ONE , volume 9 . Abstract Organochlorine insecticide hexachlorocyclohexane (HCH) has recently been classified as a ‘Persistent Organic pollutant’ by the Stockholm Convention. The LinB haloalkane dehalogenase is a key upstream enzyme in the recently evolved Lin pathway for the catabolism of HCH in bacteria. Here we report a sequence-structure-function analysis of ten naturally occurring and thirteen synthetic mutants of LinB. One of the synthetic mutants was found to have ∼80 fold more activity for β- and δ-hexachlorocyclohexane. Based on detailed biophysical calculations, molecular dynamics and ensemble docking calculations, we propose that the latter variant is more active because of alterations to the shape of its active site and increased conformational plasticity.

This article is from PLoS ONE , volume 9 . Abstract Organochlorine insecticide hexachlorocyclohexane (HCH) has recently been classified as a ‘Persistent Organic pollutant’ by the Stockholm Convention. The LinB haloalkane dehalogenase is a key upstream enzyme in the recently evolved Lin pathway for the catabolism of HCH in bacteria. Here we report a sequence-structure-function analysis of ten naturally occurring and thirteen synthetic mutants of LinB. One of the synthetic mutants was found to have ∼80 fold more activity for β- and δ-hexachlorocyclohexane. Based on detailed biophysical calculations, molecular dynamics and ensemble docking calculations, we propose that the latter variant is more active because of alterations to the shape of its active site and increased conformational plasticity.

General Biology Lecture

This article is from Molecular Microbiology , volume 93 . Abstract Some bacteria and archaea synthesize haem by an alternative pathway, which involves the sequestration of sirohaem as a metabolic intermediate rather than as a prosthetic group. Along this pathway the two acetic acid side-chains attached to C12 and C18 are decarboxylated by sirohaem decarboxylase, a heterodimeric enzyme composed of AhbA and AhbB, to give didecarboxysirohaem. Further modifications catalysed by two related radical SAM enzymes, AhbC and AhbD, transform didecarboxysirohaem into Fe-coproporphyrin III and haem respectively. The characterization of sirohaem decarboxylase is reported in molecular detail. Recombinant versions of Desulfovibrio desulfuricans, Desulfovibrio vulgaris and Methanosarcina barkeri AhbA/B have been produced and their physical properties compared. The D. vulgaris and M. barkeri enzyme complexes both copurify with haem, whose redox state influences the activity of the latter. The kinetic parameters of the D. desulfuricans enzyme have been determined, the enzyme crystallized and its structure has been elucidated. The topology of the enzyme reveals that it shares a structural similarity to the AsnC/Lrp family of transcription factors. The active site is formed in the cavity between the two subunits and a AhbA/B-product complex with didecarboxysirohaem has been obtained. A mechanism for the decarboxylation of the kinetically stable carboxyl groups is proposed.