Electronic Resources Reviews

Navigating the National Center for Biotechnology Information’s Databases on the Medicinal Chemistry of Homocystinuria

Sarah H. Jeong, MLIS
Research & Instruction Librarian-Science
Wake Forest University
jeongsh@wfu.edu

The National Center for Biotechnology Information’s (NCBI) databases are authoritative, current information sources intended for researchers, faculty, graduate students, information professionals, and the public for finding the genetic, protein, and structural molecular biological data (NCBI Resource Coordinators 2016). NCBI Gene, Nucleotide, Protein, and Structure databases are considered the four core linked, annotated genetic and protein sequence information sources curated by NCBI scientists based on the scientists’ raw data deposited into GenBank, which became publicly available in 1982 (Choudhuri 2014). MedGen is an authoritative information portal for inherited human diseases and was launched in 2012 by NCBI (Louden 2020). MedGen uses standardized terminology from “NLM’s Unified Medical Language system (UMLS®), the NIH Genetic Testing Registry (GTR®), and ClinVar” (Halavi et al. 2018). OMIM (Online Mendelian Inheritance in Man) is a curated database for finding the genotype and phenotype of inherited human diseases, which was created in 1985 through collaboration between the National Library of Medicine and the William H. Welch Medical Library of Johns Hopkins University and developed by NCBI in 1995 (About OMIM 2021). PubChem, launched in 2004 by NCBI, is a linked data repository of standardized chemical compounds and substances with provenance of chemical structures (Hähnke et al. 2018). The Bioassay section of PubChem has been a legacy tool since November 1, 2018 (About PubChem 2021). In this article, the reader will understand how to find an allele associated with the phenotype of an inherited human disease, the biomolecular pathway causing the physical manifestation of this disease, and finally, the treatment in the management of the condition.

Start by searching for Homocystinura in the NCBI MedGen database, and follow the link to the OMIM database by clicking on 236200 https://www.ncbi.nlm.nih.gov/medgen/199606 (Figure 1).

From OMIM #236200 Homocystinuria https://omim.org/entry/236200 (Figure 2), follow the link to the Gene/Locus MIM #613381.

The Cystathionine Beta-Synthase (CBS) gene https://omim.org/entry/613381 (Figure 3) encodes for a key enzyme in metabolism, and its deficiency causes Homocystinuria.

From OMIM database (https://omim.org/entry/613381) follow the link to see Allelic Variants. This takes you to: https://omim.org/entry/613381#allelicVariants

From the OMIM entry for the Cystathionine Beta-Synthase gene https://omim.org/entry/613381 (Figure 4), follow the link to the NCBI Gene database to get the canonical protein.

From the NCBI Gene record of the human cystathionine beta-synthase gene https://www.ncbi.nlm.nih.gov/gene/875 (Figure 5), look up the canonical protein (NP_000062.1) associated with Homocystinuria in the NCBI Protein database https://www.ncbi.nlm.nih.gov/protein/NP_000062.1.

You can link to 8 protein 3-D structures of cystathionine beta-synthase-like protein isoform 1 from NCBI Protein database by following the link to “See all 8 structures…” https://www.ncbi.nlm.nih.gov/protein/NP_000062.1 (Figure 6).

In NCBI Structure database, protein structure #8 https://www.ncbi.nlm.nih.gov/structure?Db=structure&DbFrom=protein&Cmd=Link&LinkName=protein_structure&LinkReadableName=Structure&IdsFromResult=4557415 (Figure 7) seems to be the wild type protein structure of human Cystathionine Beta-Synthase.

The NCBI Structure entry for PDB ID: 1JBQ Human Cystathionine Beta-Synthase https://www.ncbi.nlm.nih.gov/Structure/pdb/1JBQ (Figure 8) has links to PubChem entries for the co-factor pyridoxal 5’ phosphate https://pubchem.ncbi.nlm.nih.gov/substance/152137797 and the heme https://pubchem.ncbi.nlm.nih.gov/substance/823350, both of which are required for Cystathionine Beta-Synthase enzyme activity. On the 3-D conformer part, under ‘Interactive Chemical Structure Model’ of the PubChem record, click the Space-filling radio button to get a rendering of the molecule.

You can also search for all the relevant substrates and products and follow the link to Biomolecular Interactions and Pathways of Cystathionine (Figure 9) in the NCBI PubChem database https://pubchem.ncbi.nlm.nih.gov/compound/834.

In PubChem Section 5.1 Related Compounds with Annotations for Cystathionine https://pubchem.ncbi.nlm.nih.gov/compound/834#section=Related-Compounds-with-Annotation&fullscreen=true (Figure 10), click on “View More Rows & Details,” then sort by Create Date and follow the link to L-Cystathionine to find the biomolecular pathway that causes Homocystinuria.

In NCBI PubChem database, sort the list of related compounds of Cystathionine by “Create Date” and follow the link to L-Cystathionine (Figure 11).

From the Compound Summary of L-Cystathionine from NCBI PubChem database https://pubchem.ncbi.nlm.nih.gov/compound/439258 (Figure 12), expand the section on “Biomolecular Interactions and Pathways,” then click “Pathways.”

In PubChem Section 12.2 Pathways of L-Cystathionine https://pubchem.ncbi.nlm.nih.gov/compound/439258#section=Pathways (Figure 13), follow the link to WikiPathways database for “Methionine metabolism leading to Sulphur Amino Acids and related disorders.”

In WikiPathways database, the reaction we are looking for is homocysteine to cystathionine in methionine metabolism leading to sulfur amino acids and related disorders (Homo sapiens) https://www.wikipathways.org/index.php/Pathway:WP4292 (Figure 14), where deficiency of the Cystathionine Beta-Synthase enzyme causes Homocystinuria.

Go to the GeneReviews chapter that is linked from the entry for Classic homocystinuria in the NCBI MedGen database. https://www.ncbi.nlm.nih.gov/medgen/199606 (Figure 15).

The GeneReviews chapter covers management of the treatment for “Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency” https://pubmed.ncbi.nlm.nih.gov/20301697/ (Figure 16).

According to the GeneReviews chapter, “Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency,” the homocystinuria condition responds to vitamins B6 (pyridoxine), B-12 (Cyanocobalamin) and folate and/or a methionine restricted diet and betaine https://www.ncbi.nlm.nih.gov/books/NBK1524/#homocystinuria.Management (Figure 17).

Though not drugs in the traditional sense these are all entities that have PubChem records. Search with the terms below in PubChem Compound at https://pubchem.ncbi.nlm.nih.gov/.

Pyridoxine https://pubchem.ncbi.nlm.nih.gov/compound/1054

Cyanocobalamin does not have a 3-D structure since it is a complex but it has a 2-D rendering https://pubchem.ncbi.nlm.nih.gov/compound/5311498s

Folic Acid https://pubchem.ncbi.nlm.nih.gov/compound/135398658

L-methionine https://pubchem.ncbi.nlm.nih.gov/compound/6137

Betaine https://pubchem.ncbi.nlm.nih.gov/compound/247

Multiple articles have been written about searching NCBI databases (NCBI Resource Coordinators 2016) including GenBank (Benson et al. 2013), Gene (Brown et al. 2015), MedGen (Louden 2020), OMIM (Amberger et al. 2015; Amberger & Hamosh 2017), and PubChem (Kim et al. 2021; Kim et al. 2016) for further reading. For additional guidance on NCBI databases, please refer to the National Center for Biotechnology Information’s (NCBI) YouTube channel https://www.youtube.com/ncbinlm.

The author would like to thank Peter Cooper, Ph.D. of the National Center for Biotechnology Information for his consultation work on the search strategy.

About OMIM [Internet]. Baltimore (MD): Johns Hopkins University; c1966-2021 [cited 2021 Mar 23]. Available from https://www.omim.org/about.

About PubChem [Internet]. Legacy Bioassay Tools. Bethesda (MD): National Center for Biotechnology Information; [cited 2021 Mar 23]. Available from https://pubchemdocs.ncbi.nlm.nih.gov/legacy-bioassay-tools.

Amberger, J.S., Bocchini, C.A., Schiettecatte, F., Scott, A.F. & Hamosh, A. 2015. OMIM.org: Online Mendelian Inheritance in Man (OMIM®), an online catalog of human genes and genetic disorders. Nucleic Acids Research. 43(D1):D789-D798. DOI: 10.1093/nar/gku1205.

Amberger, J.S. & Hamosh, A. 2017. Searching Online Mendelian Inheritance in Man (OMIM): A knowledgebase of human genes and genetic phenotypes. Current Protocols in Bioinformatics. 58:1.2.1-1.2.12. DOI: 10.1002/cpbi.27.

Benson, D.A., Cavanaugh, M., Clark, K., Karsch-Mizrachi, I., Lipman, D.J., Ostell, J. & Sayers, E.W. 2013. GenBank. Nucleic Acids Research. 41(D1):D36-D42. DOI: 10.1093/nar/gks1195.

Brown, G.R., Hem, V., Katz, K.S., Ovetsky, M., Wallin, C., Ermolaeva, O., Tolstoy, I., Tatusova, T., Pruitt, K.D., Maglott, D.R., et al. 2015. Gene: A gene-centered information resource at NCBI. Nucleic Acids Research. 43(D1):D36-D42. DOI: 10.1093/nar/gku1055.

Choudhuri, S. 2014. Data, databases, data format, database search, data retrieval systems, and genome browsers. In: Choudhuri, S., editor. Bioinformatics for Beginners. Oxford (UK): Academic Press. p. 77–131.

Hähnke, V.D., Kim, S. & Bolton, E.E. 2018. PubChem chemical structure standardization. Journal of Cheminformatics. 10(1):1–40. DOI: 10.1186/s13321-018-0293-8.

Halavi, M., Maglott, D., Gorelenkov, V. & Rubinstein, W. 2018. MedGen. In: Beck, J. et al. editors. The NCBI Handbook. 2nd ed. Bethesda (MD): National Center for Biotechnology Information (US). Available from https://www.ncbi.nlm.nih.gov/books/NBK159970/.

Kim, S., Chen, J., Cheng, T., Gindulyte, A., He, J., He, S., Li, Q., Shoemaker, B.A., Thiessen, P.A., Yu, B., et al. 2021. PubChem in 2021: New data content and improved web interfaces. Nucleic Acids Research. 49(D1):D1388–D1395. DOI: 10.1093/nar/gkaa971.

Kim, S., Thiessen, P.A., Bolton, E.E., Chen, J., Fu, G., Gindulyte, A., Han, L., He, J., He, S., Shoemaker, B.A., et al. 2016. PubChem Substance and Compound databases. Nucleic Acids Research. 44(D1):D1202–D1213. DOI: 10.1093/nar/gkv951.

Louden, D.N. 2020. MedGen: NCBI’s portal to information on medical conditions with a genetic component. Medical Reference Services Quarterly. 39(2):183–191. DOI: 10.1080/02763869.2020.1726152.

NCBI Resource Coordinators. 2016. Database resources of the National Center for Biotechnology Information. Nucleic Acids Research. 44(D1):D7-19. DOI: 10.1093/nar/gkv1290.