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UniProtKB/Swiss-Prot P50336: Variant p.Asp349Ala

Protoporphyrinogen oxidase
Gene: PPOX
Variant information

Variant position:  349
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Disease [Disclaimer]
The variants are classified into three categories: Disease, Polymorphism and Unclassified.
  • Disease: Variants implicated in disease according to literature reports.
  • Polymorphism: Variants not reported to be implicated in disease.
  • Unclassified: Variants with uncertain implication in disease according to literature reports. Evidence against or in favor of a pathogenic role is limited and/or conflicting.

Residue change:  From Aspartate (D) to Alanine (A) at position 349 (D349A, p.Asp349Ala).
Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.

Physico-chemical properties:  Change from medium size and acidic (D) to small size and hydrophobic (A)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -2
The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:
  • Lowest score: -4 (low probability of substitution).
  • Highest score: 11 (high probability of substitution).
More information can be found on the following page

Involvement in disease:  Variegate porphyria (VP) [MIM:176200]: A form of porphyria. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. Variegate porphyria is the most common form of porphyria in South Africa. It is characterized by skin hyperpigmentation and hypertrichosis, abdominal pain, tachycardia, hypertension and neuromuscular disturbances. High fecal levels of protoporphyrin and coproporphyrin, increased urine uroporphyrins and iron overload are typical markers of the disease. {ECO:0000269|PubMed:10486317, ECO:0000269|PubMed:10870850, ECO:0000269|PubMed:11074242, ECO:0000269|PubMed:11102990, ECO:0000269|PubMed:11286631, ECO:0000269|PubMed:11348478, ECO:0000269|PubMed:11350188, ECO:0000269|PubMed:11474578, ECO:0000269|PubMed:12380696, ECO:0000269|PubMed:12655566, ECO:0000269|PubMed:12859407, ECO:0000269|PubMed:12922165, ECO:0000269|PubMed:14669009, ECO:0000269|PubMed:16433813, ECO:0000269|PubMed:16621625, ECO:0000269|PubMed:16922948, ECO:0000269|PubMed:16947091, ECO:0000269|PubMed:18350656, ECO:0000269|PubMed:18570668, ECO:0000269|PubMed:19320019, ECO:0000269|PubMed:21048046, ECO:0000269|PubMed:23430901, ECO:0000269|PubMed:23467411, ECO:0000269|PubMed:24073655, ECO:0000269|PubMed:8673113, ECO:0000269|PubMed:8817334, ECO:0000269|PubMed:8852667, ECO:0000269|PubMed:9541112, ECO:0000269|PubMed:9763307, ECO:0000269|PubMed:9811936}. Note=The disease is caused by mutations affecting the gene represented in this entry. Mutations leading to severe PPOX deficiency cause the rare homozygous variant form of VP. Missense mutations that preserve 10%-25% of wild-type activity may not cause clinically overt VP in heterozygotes (PubMed:9811936). Mutations with intermediate effect on catalytic activity may cause VP, but with a low clinical penetrance (PubMed:10486317). {ECO:0000269|PubMed:10486317, ECO:0000269|PubMed:9811936}.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Variant description:  In VP; decreases enzyme activity.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.



Sequence information

Variant position:  349
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  477
The length of the canonical sequence.

Location on the sequence:   QGFGHLVPSSEDPGVLGIVY  D SVAFPEQDGSPPGLRVTVML
The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.

Residue conservation: 
The multiple alignment of the region surrounding the variant against various orthologous sequences.

Human                         QGFGHLVPSS--EDPG-VLGIVYDSVAFPE--------QDGSPPGLR-----VTVML

Mouse                         QGFGHLVPSS--EDPT-VLGIVYDSVAFPE--------QDG

Bovine                        QGFGHLVPSS--EDPV-ILGIVYDSVAFPE--------QDG

Slime mold                    KGFGYLVPSK--ENQS-VIGVCFDSNTFPEFVNNNNNNNND

Baker's yeast                 QGFGYLVPKSN-KNPGKLLGVIFDSVIERNFKPLFDKLSTN

Fission yeast                 RGFGLLIPSCTPNNPNHVLGIVFDS----E--------QNN

Sequence annotation in neighborhood:  
The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:
  • Type: the type of sequence feature.
  • Positions: endpoints of the sequence feature.
  • Description: contains additional information about the feature.

TypePositionsDescription
Chain 1 – 477 Protoporphyrinogen oxidase
Mutagenesis 331 – 331 F -> A. Decreases enzyme activity by 50%.
Mutagenesis 334 – 334 L -> A. Decreases enzyme activity by 86%.
Mutagenesis 347 – 347 V -> A. Decreases enzyme activity by 45%.
Mutagenesis 368 – 368 M -> A. Decreases enzyme activity by 52%.
Helix 349 – 352


Literature citations

Structural insight into human variegate porphyria disease.
Qin X.; Tan Y.; Wang L.; Wang Z.; Wang B.; Wen X.; Yang G.; Xi Z.; Shen Y.;
FASEB J. 25:653-664(2011)
Cited for: X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) IN COMPLEX WITH FAD AND ACIFLUORFEN; CATALYTIC ACTIVITY; FUNCTION; SUBUNIT; CHARACTERIZATION OF VARIANTS VP ASP-11; THR-12; PHE-15; PRO-20; PRO-38; ALA-40; GLU-40; TRP-59; PRO-73; GLY-84; PRO-85; PRO-106; PRO-138; ASP-139; VAL-143; CYS-152; PRO-154; MET-158; HIS-168; VAL-178; VAL-205; CYS-217; GLY-224; ARG-232; ASP-282; ASN-283; PRO-295; ARG-330; ALA-332; GLY-335; CYS-348; ALA-349; PRO-350; ARG-358; ASP-397; PHE-401; PRO-433; PRO-444; ARG-448; PRO-450 AND ARG-453; MUTAGENESIS OF LEU-74; ARG-97; LEU-166; GLY-169; SER-284; VAL-290; PHE-331; LEU-334; VAL-347 AND MET-368;

Quantitative structural insight into human variegate porphyria disease.
Wang B.; Wen X.; Qin X.; Wang Z.; Tan Y.; Shen Y.; Xi Z.;
J. Biol. Chem. 288:11731-11740(2013)
Cited for: X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) OF MUTANTS GLY-59 AND GLN-59 IN COMPLEXES WITH FAD AND ACIFLUORFEN; FUNCTION; CATALYTIC ACTIVITY; MUTAGENESIS OF ARG-59; ARG-97; LEU-166; GLY-169; PHE-331; LEU-334; VAL-347 AND MET-368; CHARACTERIZATION OF VARIANTS VP TRP-59; HIS-168; ARG-330; GLY-335; ALA-349; PHE-401 AND ARG-453;

Molecular characterization of homozygous variegate porphyria.
Roberts A.G.; Puy H.; Dailey T.A.; Morgan R.R.; Whatley S.D.; Dailey H.A.; Martasek P.; Nordmann Y.; Deybach J.C.; Elder G.H.;
Hum. Mol. Genet. 7:1921-1925(1998)
Cited for: VARIANTS VP GLU-169; ALA-349; ARG-358 AND PRO-433; CHARACTERIZATION OF VARIANTS VP GLU-169; ALA-349; ARG-358 AND PRO-433;

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.