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UniProt release 2014_10

Published October 29, 2014


K for Koagulation

After several weeks of a cholesterol-free diet, chickens start bleeding. The phenotype cannot be reversed by the addition of purified cholesterol to their chow, suggesting that another compound could have been extracted along with cholesterol during food preparation. This observation made by Henrik Dam in 1929 led to the identification of a fat-soluble vitamin involved in coagulation, also known as vitamin K (K standing for Koagulationsvitamin, the original German name for this compound, since the initial observations were reported in a German journal). This discovery was awarded the Nobel prize in 1943, but vitamin K function and metabolism are still extensively studied.

In plants, vitamin K plays an essential role in photosynthesis, which is why it is particularly enriched in photosynthetic tissues, such as green leaves. In animals, vitamin K is essential for blood clotting and bone mineralization. It also prevents the calcification of arteries and other soft tissues. More recently, vitamin K has been shown to function as a mitochondrial electron carrier and to serve as a ligand for the nuclear receptor SXR, which controls the expression of genes involved in transport and metabolism of endo- and xenobiotics.

The most extensively studied vitamin K function is its role as a cosubstrate for vitamin K-dependent gamma-carboxylase (GGCX). This enzyme catalyzes gamma-carboxylation of glutamate residues in target proteins. The modification activates several blood factor proteins and leads to initiation of the blood coagulation cascade. Widely used anticoagulant drugs, called coumarins, take advantage of this property and act as vitamin K antagonists. For example, warfarin is thought to inhibit vitamin K epoxide reductase complex subunit 1 (VKORC1), blocking vitamin K recycling, hence depleting active vitamin K stores. Although life-saving, the use of warfarin is quite tricky, as inadequate dosage may have dramatic consequences, either embolism or thrombosis (underdosage), or potentially fatal hemorrhage (overdosage). Interindividual genetic variations greatly affect warfarin efficiency. Polymorphisms within VKORC1 and CYP2C9, a cytochrome P450 family member involved in coumarin inactivation, together account for approximately 30% of population dose variance. A genetic variant p.Val433Met in another P450 family member, CYP4F2, has also been reported to increase warfarin requirements. CYP4F2 has recently been shown to catalyze vitamin K omega-hydroxylation, a key step in vitamin K degradation. The p.Val433Met polymorphism produces a decrease of CYP4F2 protein in the liver. Lower CYP4F2 levels likely lead to an increase in hepatic vitamin K levels, hence more molecules that warfarin must antagonize, resulting in coumarin resistance in individuals bearing this polymorphism.

As of this release, an updated version of the UniProtKB/Swiss-Prot CYP4F2 entry is available. Proteins undergoing gamma-carboxylation can be retrieved using the keyword Gamma-carboxyglutamic acid.

UniProtKB news

Change of the cross-reference ArrayExpress to ExpressionAtlas

The Expression Atlas database provides information on baseline and differential gene expression patterns under different biological conditions. Experiments in Expression Atlas are selected from the ArrayExpress database of functional genomics experiments. Because UniProtKB entries cross-reference only this subset of experiments, we have changed the resource abbreviation for these cross-references from ArrayExpress to ExpressionAtlas. We have at the same time added a field to indicate the type of expression patterns for which information can be found in the ExpressionAtlas (see examples below).

Text format

Example: P15822

DR   ExpressionAtlas; P15822; baseline and differential.

XML format

Example: P15822

<dbReference type="ExpressionAtlas" id="P15822"/>
  <property type="expression patterns" value="baseline and differential"/>

RDF format

Example: P15822

  rdfs:seeAlso <> .
  rdf:type Resource ;
  up:database <> ;
  rdfs:comment "baseline and differential" .

Changes to the controlled vocabulary of human diseases

New diseases:

Modified diseases:

Deleted diseases:

  • Amelogenesis imperfecta and gingival fibromatosis syndrome
  • Mental retardation, X-linked 59

Changes to the controlled vocabulary for PTMs

New terms for the feature key ‘Modified residue’ (‘MOD_RES’ in the flat file):

  • (4R)-5-hydroxyleucine
  • (4R)-5-oxoleucine

Deleted term:

  • 5-methoxythiazole-4-carboxylic acid (Val-Cys)