GLRX5

{{Short description|Protein-coding gene in the species Homo sapiens}}

Glutaredoxin 5, also known as GLRX5, is a protein which in humans is encoded by the GLRX5 gene located on chromosome 14.{{cite journal | vauthors = Wingert RA, Galloway JL, Barut B, Foott H, Fraenkel P, Axe JL, Weber GJ, Dooley K, Davidson AJ, Schmid B, Schmidt B, Paw BH, Shaw GC, Kingsley P, Palis J, Schubert H, Chen O, Kaplan J, Zon LI | title = Deficiency of glutaredoxin 5 reveals Fe-S clusters are required for vertebrate haem synthesis | journal = Nature | volume = 436 | issue = 7053 | pages = 1035–39 | date = Aug 2005 | pmid = 16110529 | doi = 10.1038/nature03887 | bibcode = 2005Natur.436.1035W | s2cid = 4333813 }} This gene encodes a mitochondrial protein, which is evolutionarily conserved. It is involved in the biogenesis of iron- sulfur clusters, which are required for normal iron homeostasis. Mutations in this gene are associated with autosomal recessive pyridoxine-refractory sideroblastic anemia.{{Cite web|url=https://www.ncbi.nlm.nih.gov/gene/51218|title=GLRX5 glutaredoxin 5 [Homo sapiens (human)] - Gene - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2016-10-26}}

Structure

The GLRX5 gene contains 2 exons and encodes for a protein that is 13 kDa in size. The protein is highly expressed in erythroid cells.{{cite journal |vauthors=Ye H, Jeong SY, Ghosh MC, Kovtunovych G, Silvestri L, Ortillo D, Uchida N, Tisdale J, Camaschella C, Rouault TA |title=Glutaredoxin 5 deficiency causes sideroblastic anemia by specifically impairing heme biosynthesis and depleting cytosolic iron in human erythroblasts |journal=J. Clin. Invest. |volume=120 |issue=5 |pages=1749–61 |year=2010 |pmid=20364084 |pmc=2860907 |doi=10.1172/JCI40372 }} Crystal structure of the GLRX5 protein reveals that the protein likely exists as a tetramer with two Fe-S clusters buried in the interior.{{cite journal |vauthors=Johansson C, Roos AK, Montano SJ, Sengupta R, Filippakopoulos P, Guo K, von Delft F, Holmgren A, Oppermann U, Kavanagh KL |title=The crystal structure of human GLRX5: iron-sulfur cluster co-ordination, tetrameric assembly and monomer activity |journal=Biochem. J. |volume=433 |issue=2 |pages=303–11 |year=2011 |pmid=21029046 |doi=10.1042/BJ20101286 |hdl=10616/41576 |url=https://hal.science/hal-00549898 |hdl-access=free }}

Function

GLRX5 is a mitochondrial protein, found in mitochondrial matrix and it is conserved evolutionarily and plays a role in the formation of iron-sulfur clusters, which function to maintain iron homeostasis within the mitochondria and in the cell. GLRX5 is required for the steps in haem synthesis that involves mitochondrial enzymes,{{cite journal |vauthors=Wingert RA, Galloway JL, Barut B, Foott H, Fraenkel P, Axe JL, Weber GJ, Dooley K, Davidson AJ, Schmid B, Schmidt B, Paw BH, Shaw GC, Kingsley P, Palis J, Schubert H, Chen O, Kaplan J, Zon LI |title=Deficiency of glutaredoxin 5 reveals Fe-S clusters are required for vertebrate haem synthesis |journal=Nature |volume=436 |issue=7053 |pages=1035–39 |year=2005 |pmid=16110529 |doi=10.1038/nature03887 |bibcode=2005Natur.436.1035W |s2cid=4333813 }} and is therefore involved in hematopoiesis. GLRX5 activity is required for normal regulation of hemoglobin synthesis by the iron-sulfur protein ACO1. The function of GLRX5 is highly conserved evolutionarily.{{cite journal |vauthors=Camaschella C, Campanella A, De Falco L, Boschetto L, Merlini R, Silvestri L, Levi S, Iolascon A |title=The human counterpart of zebrafish shiraz shows sideroblastic-like microcytic anemia and iron overload |journal=Blood |volume=110 |issue=4 |pages=1353–8 |year=2007 |pmid=17485548 |doi=10.1182/blood-2007-02-072520 |doi-access=free }}

Clinical significance

Mutations in the GLRX5 gene have been associated with sideroblastic anemia,{{cite journal | vauthors = Camaschella C | title = Recent advances in the understanding of inherited sideroblastic anaemia | journal = British Journal of Haematology | volume = 143 | issue = 1 | pages = 27–38 | date = Oct 2008 | pmid = 18637800 | doi = 10.1111/j.1365-2141.2008.07290.x | doi-access = | s2cid = 11780617 }} variant glycine encephalopathy (also known as non-ketotic hyperglycinemia, NKH).{{cite journal | vauthors = Baker PR, Friederich MW, Swanson MA, Shaikh T, Bhattacharya K, Scharer GH, Aicher J, Creadon-Swindell G, Geiger E, MacLean KN, Lee WT, Deshpande C, Freckmann ML, Shih LY, Wasserstein M, Rasmussen MB, Lund AM, Procopis P, Cameron JM, Robinson BH, Brown GK, Brown RM, Compton AG, Dieckmann CL, Collard R, Coughlin CR, Spector E, Wempe MF, Van Hove JL | title = Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5 | journal = Brain | volume = 137 | issue = Pt 2 | pages = 366–79 | date = Feb 2014 | pmid = 24334290 | doi = 10.1093/brain/awt328 | pmc = 3914472 }} as well as pyridoxine-refractory, autosomal recessive anemia (PRARSA). Cells with mutations in GLRX5 activity show deficiency in Fe-S cluster synthesis, which is likely causative of the observed symptoms.

GLRX5

Structure

Function

Clinical significance

See also

References

Further reading