CHEM 342 - Introduction to Biochemistry

Hemoglobinopathy Assignment - Due Last Friday of the Semester

Linus Pauling introduced the concept of molecular disease by demonstrating that the gene for sickle cell anemia was directly related to a chemical alteration of hemoglobin in the red blood cells of affected individuals. A few years later, Vernon Ingram identified a single amino acid replacement at position 6 of the beta chains of sickle cell hemoglobin (HbS) and showed that the sequence of the remaining 145 amino acids of the beta chains and all 141 amino acids in the alpha chains of hemoglobin were unchanged compared to normal hemoglobin (HbA). Subsequently, others determined the exact nucleotide substitution mutation in the beta globin gene possessed by sickle cell patients.

These discoveries prompted a stampede of sorts to discover other hemoglobin variants and the corresponding mutations in DNA. There are now on the order of 1000 different mutations known to affect the amino acid sequence or production of hemoglobin. While many of these are single-base-substitution mutations, deletions, and insertions that have little or no clinical effects, the consequences of others vary from benign to severe, as in the case of thalassemias. Many medical biochemists have made a career studying these usually rare hemoglobinopathies.

Using a list of hemoglobinopathies (alpha-chain, beta-chain, thalassemias), pick an interesting example to investigate as the basis for a 5+ page, double-spaced, well-organized report. Select a variant that no one else in class has selected. Your report should have the following elements:

To prepare for this assignment, each group should arrange a time before April 25 to meet for 30-60 minutes with Catherine Wojewodzki, a science librarian in 117C Morris Library (831-4240, or Cathyw at udel.edu) who is familiar with this project and can provide assistance in tracking down the information you need. In the past, students have had problems because they did not take full advantage of the resources available.   You will need to develop these  library research skills as part of your undergraduate education. (They go well beyond "Googling" the internet.)

This assignment will be evaluated for its composition, content, clarity of presentation, and depth of your analysis. An "A paper" must go beyond simple reporting of information.  For example, a molecular graphics representation of your hemoglobin variant showing the location of any mutational modification, but make sure it shows something worth seeing. Remember, this should be your synthesis of the information, not a paraphrasing of the words of others. Late papers will not be accepted wityhout a grade penalty.


Other Options: Students who would rather explore aspects of hemoglobin function, evolution, or properties of unusual hemoglobins from other sources may do so in consultation with Dr. White. There are related topics available such as Glucose-6-P deficiency (favism).

Suggestions:
1. Nobel Prize winner, Max Perutz (1914-2002), spent 20 years working on the X-ray crystallography of hemoglobin before he finally determined its three-dimentional structure in 1957. There after he spent much of the rest of his life studying the structure of interesting hemoglobin variants. One strategy you might try is to search and examine the publications of Max Perutz on PubMed or the Web of Science. Remember, you can often get full text copies through the University of Delaware's electronic journal subscriptions. You may also find some of the sites linked to the course home page of use.

2. Log on to one of the protein data bases and explore their reference lists and tabulations of hemoglobin varaints. Some data bases include: NCBI (National Center for Biomedical Information), PDB (Protein Data Bank, or Swiss-Prot (Swiss protein data base). Simply start your search at any of these by typing in "human hemoglobin" and follow the links of interest.

3. Feel free to discuss your ideas and any difficulties you have with me (Dr. White) preferably well before the due date..

Making your request: All requests must be cleared by sending an e-mail message to Dr. White who will check to be sure no one else in the class has selected the same topic. Your request should be brief but include the name of the hemoglobin variant, the nature of the mutation, at least two literature citations to relvant references, and any medical consequences of the condition. Selections should be made on or before the second Friday in April after Spring Break.  HbC and HbS are not available.

Hemoglobin variants taken as of 3:00
PM, 28 April 2008. Student initials after variant.
 
Hb Bushwick  (beta G74V) KS
Hb J-Baltimore (beta G16D)  AD Ascaris lumbricoides Hb  AS
Hb Hope (betaG136D) CS
Hb E  (beta E26K) CB Hb O-Arab (beta E121K) AV Methemoglobinemia  BO
Hb Kenya (gamma-beta hybrid) DM
Hb Hiroshima (beta H143D) LK
Hb D-Punjab (beta E121Q) JB Hb M-Iwate (alpha H87Y) JG Hb Deer Lodge (beta H2R) KG
Hb H (beta tetramer)  SL
Hb Chapel Hill  (alpha D74G) BW
Hb J-Capetown (alpha2 R92Q) AdB
Hb Sanerne (beta H143P+) KD
Hb Leiden (beta E6or7Term) AsB Hb Barts (alpha thalassemia)  JN Hb Constant Spring (alpha Trm142Q) AnB Hb Jamaca Plain  (beta E6V+L68F) TH
Hb J Calabria (beta G64D) AG
Hb G-Philadelphia (alpha N68K) DC Hb Lepore Boston (delta-beta hybrid) SU
Hb St. Luke's (alpha P95R) TB
MC
DK




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Last updated: 13 May 2008 by Hal White [halwhite at udel.edu]
Copyright 2008 Harold B. White, Department of Chemistry and Biochemistry, University of Delaware