Biomedical subjects

L Widjaja

Publications and source records attributed to L Widjaja.

3 recordsLinked to original sources

PubMed2002

Stroke disease management--a framework for comprehensive stroke care.

Disease management is an approach to patient care that coordinates medical resources for the patient across the entire healthcare delivery system throughout the lifetime of the patient with the disease. Stroke is suitable for disease management as it is a well-known disease with a high prevalence, high cost, variable practice pattern, poor clinical outcome, and managed by a non-integrated healthcare system. It has measurable and actionable outcomes, with available local expertise and support of the Ministry of Health. Developing the programme requires a multidisciplinary team, baseline data on target populations and healthcare services, identification of core components, collaboration with key stakeholders, development of evidence-based clinical practice guidelines and carepaths, institution of care coordinators, use of information technology and continuous quality improvement to produce an effective plan. Core components include public education, risk factor screening and management, primary care and specialist clinics, acute stroke units, inpatient and outpatient rehabilitation facilities, and supportive community services including medical, nursing, therapy, home help and support groups for patients and carers. The family physician plays a key role. Coordination of services is best done by a network of hospital and community-based care managers, and is enhanced by a coordinating call centre. Continuous quality improvement is required, with audit of processes and outcomes, facilitated by a disease registry. Pitfalls include inappropriate exclusion of deserving patients, misuse, loss of physician and patient independence, over-estimation of benefits, and care fragmentation. Collaboration and cooperative among all parties will help ensure a successful and sustainable programme.

Comprehensive Health Care↗

PubMed1999

Proton transfer from histidine 244 may facilitate the 1,2 rearrangement reaction in coenzyme B(12)-dependent methylmalonyl-CoA mutase.

Methylmalonyl-CoA mutase is an adenosylcobalamin-dependent enzyme that catalyzes the 1,2 rearrangement of methylmalonyl-CoA to succinyl-CoA. This reaction results in the interchange of a carbonyl-CoA group and a hydrogen atom on vicinal carbons. The crystal structure of the enzyme reveals the presence of an aromatic cluster of residues in the active site that includes His-244, Tyr-243, and Tyr-89 in the large subunit. Of these, His-244 is within hydrogen bonding distance to the carbonyl oxygen of the carbonyl-CoA moiety of the substrate. The location of these aromatic residues suggests a possible role for them in catalysis either in radical stabilization and/or by direct participation in one or more steps in the reaction. The mechanism by which the initially formed substrate radical isomerizes to the product radical during the rearrangement of methylmalonyl-CoA to succinyl-CoA is unknown. Ab initio molecular orbital theory calculations predict that partial proton transfer can contribute significantly to the lowering of the barrier for the rearrangement reaction. In this study, we report the kinetic characterization of the H244G mutant, which results in an acute sensitivity of the enzyme to oxygen, indicating the important role of this residue in radical stabilization. Mutation of His-244 leads to an approximately 300-fold lowering in the catalytic efficiency of the enzyme and loss of one of the two titratable pK(a) values that govern the activity of the wild type enzyme. These data suggest that protonation of His-244 increases the reaction rate in wild type enzyme and provides experimental support for ab initio molecular orbital theory calculations that predict rate enhancement of the rearrangement reaction by the interaction of the migrating group with a general acid. However, the magnitude of the rate enhancement is significantly lower than that predicted by the theoretical studies.

Binding Sites↗

PubMed1999

Assignment of enzymatic functions to specific regions of the PLP-dependent heme protein cystathionine beta-synthase.

Cystathionine beta-synthase is a unique heme protein that catalyzes a pyridoxal phosphate (or PLP)-dependent beta-replacement reaction. The reaction involves the condensation of serine and homocysteine and constitutes one of the two major avenues for detoxification of homocysteine in mammals. The enzyme is allosterically regulated by S-adenosylmethionine (AdoMet). In this study, we have characterized the kinetic, spectroscopic, and ligand binding properties of a truncated catalytic core of cystathionine beta-synthase extending from residues 1 through 408 in which the C-terminal 143 residues have been deleted. This is similar to a natural variant of the protein that has been described in a homocystinuric patient in which the predicted peptide is 419 amino acids in length. Truncation leads to the formation of a dimeric enzyme in contrast to the tetrameric organization of the native enzyme. Some of the kinetic properties of the truncated enzyme are different from the full-length form, most notably, significantly higher K(m)s for the two substrates, and loss of activation by AdoMet. This is paralleled by the absence of AdoMet binding to the truncated form, whereas four AdoMet molecules bind cooperatively to the full-length tetrameric enzyme with a K(d) of 7. 4 microM. Steady-state kinetic analysis indicates that the order of substrate addition is important. Thus, preincubation of the enzyme with homocysteine leads to a 2-fold increase in V(max) relative to preincubation of the enzyme with serine. Since the intracellular concentration of serine is significantly greater than that of homocysteine, the physiological significance of this phenomenon needs to be considered. Based on ligand binding studies and homology searches with protein sequences in the database, we assign residues 68-209 as being important for PLP binding, residues 241-341 for heme binding, and residues 421-469 for AdoMet binding.

Amino Acid Sequence↗