We are a Bioinformatics lab with an interest in how mutations affect protein structure and function. We are not a clinical group and cannot offer any assistance with the clinical aspects of living with Favism.
These pages are dedicated to Dr. Veronica Lam who died in the Asian tsunami disaster on 26th December 2004
Hereditary deficiency in human Glucose-6-phosphate dehydrogenase (G6PD)is estimated to affect about 400 million worldwide. The highest prevalence rates are found in tropical Africa, the Middle East, tropical and sub-tropical Asia, some parts of the Mediterranean and in Papua New Guinea.
The web-accessible database is an integration of up-to-date mutational and structural data from various genetic and structural databases (Genbank, Protein Data Bank, etc.) and latest publications. An automated analysis of mutations likely to have a significant impact on the structure of the protein has also been performed. This procedure identifies mutations which distort secondary structure, destroy hydrogen bonding and electrostatic interactions or simply cause bad clashes. Residues involved in the active site and the dimer interface and residues conserved among the G6PDs of different species are also identified.
This database can provide both science researchers and clinicians insights into the molecular aspects and clinical significance of G6PD deficiency. It also facilitates the understanding of the structure and function relationships of the enzyme.
Note that the data in the database have not been updated since 2004.
The G6PD gene consists of 13 exons and 12 introns which are spread over a region of >100kb on the X chromosome. Therefore G6PD deficiency is an X-linked genetic defect in which most sufferers of the disease are male. G6PD deficiency is also thought to have a link with malaria in many studies.
G6PD (EC code 126.96.36.199) is the first enzyme of the pentose phosphate pathway, converting alpha-D-glucose-6-phospate from Glycolysis into D-Glucono-1,5-lactone-6-phosphate, and is also involved in Glutathione metabolism
The monomer of human G6PD consists of 514 amino acids and is of molecular weight 59kDa. The active human enzyme exists in an equilibrium between dimer and tetramer, which is affected by pH and ionic strength. Recent determination of the first 3-dimensional crystal structure of human G6PD demonstrates clearly the importance of a structural NADP+ bound to each of the monomeric enzyme molecules for protein stability and provides new insights into the mechanisms of G6PD deficiency. The enzyme structure has two domains, usually termed 'the NADP binding domain' and the 'large domain'. The active site is located between the two domains. The NADP binding domain adopts a Rossman fold whereas the large domain has an alpha-beta fold (see CATH).
The most common clinical manifestations of G6PD deficiency are neonatal jaundice and acute haemolytic anaemia; the latter can be triggered by infections, the ingestion of fava bean (favism), some drugs (e.g. anti-malarials) and some Chinese herbal medicines. In some cases, the neonatal jaundice is severe enough to cause death or permanent neurological damage. In a proportion of cases, these manifestations may be life-threatening but fortunately, apart from these episodes of haemolytic anaemia, most G6PD deficient individuals are usually asymptomatic. A very small proportion of G6PD individuals have chronic haemolytic anaemia which can be severe. Total loss of G6PD activity is fatal.
Most of the 127 different mutations, identified to-date, are classified from Class I to Class IV (WHO classification),according to the severity/type of clinical manifestations:-
- Class I : severe enzyme deficiency with chronic non-spherocytic haemolytic anaemia (CNSHA);
- Class II : severe enzyme deficiency with less than 10% of the normal activity;
- Class III : mild to moderate enzyme deficiency (10 to 60% of normal activity);
- Class IV : very mild or almost normal enzyme activity (>60% normal activity and no clinical problem).
Screening of newborns is carried out in some parts of the world to identify those at risk; parents are counselled to avoid the potential offending agents. This is one of the most important aspects of managing the disease since there is still no cure available.