Summary of the human

Domain	Polypeptide^a/Nucleotide^b	Function^c	SNP^d	Exone	Allele	aa change^f	pI^g
1	27-173 (147 aa)/79-519 (441 bp, exon 2-6)	N-terminal Fe-S clusters	NoneT85C A496G	2 6	*9A -	C29R M166V	8.20 8.42 8.20
2	174-286 (113 aa)/520-858 (339 bp, exon 6-9)442-524 (83 aa)/ 1324-1572 (249 bp, exon 11-13)	FAD bindingFAD binding	NoneG623A A775G T1391C	6 8 12	New New New	R208Q K259E V464A	4.85 4.70 4.61 4.85
3	287-441 (155 aa)/ 859-1323 (465 bp, exon 9-11)	NADPH binding	None G1236A	11	New	E412^h	7.25 7.25
4	525-847 (323 aa)/ 1573-2541 (969 bp, exon 13-20)	FMN/5-FU binding	None G1601A A1627G T1896C In 14 G1Ai G2194A	13 13 14 14 18	4 5B - 2A 6	S534N I543V F632^h exon 14^j V732I	5.41 5.41 5.41 5.41 6.51 5.41
5	1-26 (26 aa)/1-78 (78 bp, exon 1-2) 848-1025 (178 aa)/ 2542-3075 (534 bp, exon 20-23)
5		C-terminal Fe-S clusters	NoneA2846T G2858C	22 22	- New	D949V C953S	8.038.20 8.08

^aAmino acid position; ^bBase pair numbering based on cDNA sequence: position 1 is A of the start codon ATG; ^cThe function of the domain; ^dSNP, single nucleotide polymorphism, on mRNA; ^eExon containing SNP; ^fAmino acid substitution on DPD protein; ^gIsoelectric point (pI) of each domain with or without SNP calculated using EMBOSS program; ^hSilent mutation; ⁱThe DPYD splicing site mutation; ^jdeletion of 55 amino acids (residues 581-635).

Table 1: Summary of the human dihydropyrimidine dehydrogenase (DPD) domain structure, function, and SNPs associated with severe 5-FU toxicity (mainly leucopenia and mucositis) reported by the German Clinical Study Group (Appendix Table A7) [2]. With 92% homology to pig liver DPD (NP_999209.1; see Table 2), the human DPD (NP_000101.2) subunit is also composed of five domains and their distinct functions.