FCCC LOGO Faculty Publications
Jaffe EK , Stith L
ALAD porphyria is a conformational disease
American Journal of Human Genetics. 2007 Feb;80(2) :329-337
PMID: ISI:000243729500012   
Back to previous list
ALAD porphyria is a rare porphyric disorder, with five documented compound heterozygous patients, and it is caused by a profound lack of porphobilinogen synthase (PBGS) activity. PBGS, also called "delta-aminolevulinate dehydratase," is encoded by the ALAD gene and catalyzes the second step in the biosynthesis of heme. ALAD porphyria is a recessive disorder; there are two common variant ALAD alleles, which encode K59 and N59, and eight known porphyria-associated ALAD mutations, which encode F12L, E89K, C132R, G133R, V153M, R240W, A274T, and V275M. Human PBGS exists as an equilibrium of functionally distinct quaternary structure assemblies, known as "morpheeins," in which one functional homo-oligomer can dissociate, change conformation, and reassociate into a different oligomer. In the case of human PBGS, the two assemblies are a high-activity octamer and a low-activity hexamer. The current study quantifies the morpheein forms of human PBGS for the common and porphyria-associated variants. Heterologous expression in Escherichia coli, followed by separation of the octameric and hexameric assemblies on an ion-exchange column, showed that the percentage of hexamer for F12L (100%), R240W (80%), G133R (48%), C132R (36%), E89K (31%), and A274T (14%)was appreciably larger than for the wild-type proteins K59 and N59 (0% and 3%, respectively). All eight porphyria-associated variants, including V153M and V275M, showed an increased propensity to form the hexamer, according to a kinetic analysis. Thus, all porphyria-associated human PBGS variants are found to shift the morpheein equilibrium for PBGS toward the less active hexamer. We propose that the disequilibrium of morpheein assemblies broadens the definition of conformational diseases beyond the prion disorders and that ALAD porphyria is the first example of a morpheein-based conformational disease.
ISI Document Delivery No.: 129KX Times Cited: 0 Cited Reference Count: 47 Cited References: AKAGI R, 1999, BRIT J HAEMATOL, V106, P931 AKAGI R, 2000, BLOOD, V96, P3618 AKAGI R, 2000, HEPATOLOGY, V31, P704 AKAGI R, 2006, BRIT J HAEMATOL, V132, P237 AKAGI R, 2006, MOL GENET METAB, V87, P329 BATTISTUZZI G, 1981, ANN HUM GENET, V45, P223 BREINIG S, 2003, NAT STRUCT BIOL, V10, P757 CARRELL RW, 1997, LANCET, V350, P134 DOSS M, 1972, Z KLIN CHEM KLIN BIO, V10, P230 DOSS MO, 2004, J INHERIT METAB DIS, V27, P529 FISHBEIN L, 1998, SCI TOTAL ENVIRON, V217, P71 FUJITA H, 1995, NIPPON RINSHO, V53, P1408 GROSS M, 1999, J BIOL CHEM, V274, P3125 GROSS U, 1998, CLIN CHEM, V44, P1892 GUO GG, 1994, J BIOL CHEM, V269, P12399 HAMOSH A, 2000, HUM MUTAT, V15, P57 ISHIDA N, 1992, J CLIN INVEST, V89, P1431 JAFFE EK, 2000, ACTA CRYSTALLOGR D 2, V56, P115 JAFFE EK, 2000, J BIOL CHEM, V275, P2619 JAFFE EK, 2001, J BIOL CHEM, V276, P1531 JAFFE EK, 2004, BIOORG CHEM, V32, P316 JAFFE EK, 2005, TRENDS BIOCHEM SCI, V30, P490 LIEDGENS W, 1980, Z NATURFORSCH C, V35, P958 MARUNO M, 2001, BLOOD, V97, P2972 MONTENEGRO MF, 2006, CLIN CHIM ACTA, V367, P192 MURAOKA A, 1995, KOBE J MED SCI, V41, P23 PARRA EJ, 1995, AM J PHYS ANTHROPOL, V97, P381 PONKA P, 1999, AM J MED SCI, V318, P241 SAKAMOTO D, 2004, MECH DEVELOP, V121, P747 SASSA S, 1992, T ASSOC AM PHYSICIAN, V105, P250 SASSA S, 1998, SEMIN LIVER DIS, V18, P95 SASSA S, 2002, PHOTODERMATOL PHOTO, V18, P56 SHEMIN D, 1953, J AM CHEM SOC, V75, P4873 SHEMIN D, 1955, J BIOL CHEM, V215, P613 SHEMIN D, 1972, ENZYMES, P323 SHEN XM, 2001, ENVIRON RES, V85, P185 SITHISARANKUL P, 1997, AM J IND MED, V32, P15 SUZEN HS, 2004, BIOCHEM GENET, V42, P461 TANG L, 2005, J BIOL CHEM, V280, P15786 TANG L, 2006, J BIOL CHEM, V281, P6682 THUNELL S, 1987, J CLIN CHEM CLIN BIO, V25, P5 VANHEYNINGEN S, 1971, BIOCHEMISTRY-US, V10, P4676 WETMUR JG, 1991, AM J HUM GENET, V49, P757 WETMUR JG, 1991, ENVIRON RES, V56, P109 WEUVE J, 2006, OCCUP ENVIRON MED, V63, P746 YANO Y, 1998, RYOIKIBETSU SHOKOGUN, V19, P139 ZHENG Y, 2001, ZHONGHUA YU FANG YI, V35, P16