Investigation of Homocystinuria-Associated Mutations in the Active Site of Cystathionine β-Synthase
Bibliographic record
Abstract
Homocystinuria is an inherited autosomal recessive disorder that affects an individual's ability to metabolize the L-methionine derivative L-homocysteine.Cystathionine β-synthase (CBS) catalyzes the condensation of L-homocysteine and Lserine in the first step of the reverse transsulfuration pathway, which shunts excess Lhomocysteine to L-cysteine biosynthesis.More than 100 mutations of the CBS gene have been associated with homocystinuria.Treatment for this disease includes supplementation with vitamin B 6 and/or betaine and restriction of dietary L-methionine.Refinement of these therapeutic regimes will be enabled by an enhanced understanding of the distinct effects of homocystinuria-associated mutations as well as detailed characterization of the roles of the residues and hydrogen bonding networks in the enzyme active site.This study: (1) probed the role of active site residues D319, S323 and Y324 in the positioning of the pyridoxal 5'-phosphate cofactor of the model yeast CBS enzyme and (2) investigated a set of 11 homocystinuria-associated mutations in the context of human CBS.In the first study, substitution of D319 with alanine, removing only the carboxylate moiety of the side chain, eliminated activity, while the S323A and Y324F variants, each lacking the side chain hydroxyl group, had negligible effect on the kinetic parameters, compared to the wild-type enzyme.Residue G148 provides the mobile loop the flexibility to transition between the open and closed active site conformations.Residues E176, K384 and G307 are involved in maintaining a catalytically productive active site architecture.Residues T257 and G259 serve critical roles in PLP binding and in the bi-directional communication between the heme and PLP iii cofactors.Residues G305 and S349 also participate in positioning of the PLP cofactor.Understanding the structure-function relationships that underlie the molecular basis for each distinct homocystinuria-associated mutation of CBS provides insight that can be used to refine treatment for patients with homocystinuria.where he stands in moments of comfort and convenience, but where he stands at times of challenge and controversy".The challenge of completing my M.Sc.degree would not have been possible without the rays of light that have guided me through this tunnel.Firstly, I would like to thank Dr. Susan M. Aitken for giving me the opportunity to work in her lab as an undergraduate albeit my grades signified that I did not deserve nor earned that opportunity.Yet, you helped me realized that research is my passion.Without your insight, I would not be in the position that I am in right now.I still have a lot to learn when it comes to being a researcher but you have helped me get this far and I know you will continue to guide me to becoming the researcher I want to be during my tenure as a Ph.D. candidate in your lab.I would like to extend
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".