BACKGROUND: Standard numbering schemes for families of homologous proteins allow 
for the unambiguous identification of functionally and structurally relevant 
residues, to communicate results on mutations, and to systematically analyse 
sequence-function relationships in protein families. Standard numbering schemes 
have been successfully implemented for several protein families, including 
lactamases and antibodies, whereas a numbering scheme for the structural family 
of thiamine-diphosphate (ThDP) -dependent decarboxylases, a large subfamily of 
the class of ThDP-dependent enzymes encompassing pyruvate-, benzoylformate-, 
2-oxo acid-, indolpyruvate- and phenylpyruvate decarboxylases, benzaldehyde 
lyase, acetohydroxyacid synthases and 
2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexadiene-1-carboxylate synthase 
(MenD) is still missing.Despite a high structural similarity between the members 
of the ThDP-dependent decarboxylases, their sequences are diverse and make a 
pairwise sequence comparison of protein family members difficult.
RESULTS: We developed and validated a standard numbering scheme for the family 
of ThDP-dependent decarboxylases. A profile hidden Markov model (HMM) was 
created using a set of representative sequences from the family of 
ThDP-dependent decarboxylases. The pyruvate decarboxylase from S. cerevisiae 
(PDB: 2VK8) was chosen as a reference because it is a well characterized enzyme. 
The crystal structure with the PDB identifier 2VK8 encompasses the structure of 
the ScPDC mutant E477Q, the cofactors ThDP and Mg(2+) as well as the substrate 
analogue (2S)-2-hydroxypropanoic acid. The absolute numbering of this reference 
sequence was transferred to all members of the ThDP-dependent decarboxylase 
protein family. Subsequently, the numbering scheme was integrated into the 
already established Thiamine-diphosphate dependent Enzyme Engineering Database 
(TEED) and was used to systematically analyze functionally and structurally 
relevant positions in the superfamily of ThDP-dependent decarboxylases.
CONCLUSIONS: The numbering scheme serves as a tool for the reliable sequence 
alignment of ThDP-dependent decarboxylases and the unambiguous identification 
and communication of corresponding positions. Thus, it is the basis for the 
systematic and automated analysis of sequence-encoded properties such as 
structural and functional relevance of amino acid positions, because the 
analysis of conserved positions, the identification of correlated mutations and 
the determination of subfamily specific amino acid distributions depend on 
reliable multisequence alignments and the unambiguous identification of the 
alignment columns. The method is reliable and robust and can easily be adapted 
to further protein families.