6cer: Difference between revisions

From Proteopedia
Jump to navigation Jump to search
← Older editNewer edit →
No edit summary
No edit summary
Line 1: Line 1:


==Human pyruvate dehydrogenase complex E1 component V138M mutation==
==Human pyruvate dehydrogenase complex E1 component V138M mutation==
<StructureSection load='6cer' size='340' side='right' caption='[[6cer]], [[Resolution|resolution]] 2.69&Aring;' scene=''>
<StructureSection load='6cer' size='340' side='right'caption='[[6cer]], [[Resolution|resolution]] 2.69&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6cer]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CER OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CER FirstGlance]. <br>
<table><tr><td colspan='2'>[[6cer]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CER OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CER FirstGlance]. <br>
Line 25: Line 25:


==See Also==
==See Also==
*[[Pyruvate dehydrogenase|Pyruvate dehydrogenase]]
*[[Pyruvate dehydrogenase 3D structures|Pyruvate dehydrogenase 3D structures]]
== References ==
== References ==
<references/>
<references/>
Line 31: Line 31:
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Arjunan, P]]
[[Category: Arjunan, P]]
[[Category: Furey, W]]
[[Category: Furey, W]]

Revision as of 15:49, 25 December 2019

Human pyruvate dehydrogenase complex E1 component V138M mutationHuman pyruvate dehydrogenase complex E1 component V138M mutation

Structural highlights

6cer is a 8 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:,
Gene:PDHA1, PHE1A (HUMAN), PDHB, PHE1B (HUMAN)
Activity:Pyruvate dehydrogenase (acetyl-transferring), with EC number 1.2.4.1
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[ODPA_HUMAN] Defects in PDHA1 are a cause of pyruvate dehydrogenase E1-alpha deficiency (PDHAD) [MIM:312170]. An enzymatic defect causing primary lactic acidosis in children. It is associated with a broad clinical spectrum ranging from fatal lactic acidosis in the newborn to chronic neurologic dysfunction with structural abnormalities in the central nervous system without systemic acidosis.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] Defects in PDHA1 are the cause of X-linked Leigh syndrome (X-LS) [MIM:308930]. X-LS is an early-onset progressive neurodegenerative disorder with a characteristic neuropathology consisting of focal, bilateral lesions in one or more areas of the central nervous system, including the brainstem, thalamus, basal ganglia, cerebellum, and spinal cord. The lesions are areas of demyelination, gliosis, necrosis, spongiosis, or capillary proliferation. Clinical symptoms depend on which areas of the central nervous system are involved. The most common underlying cause is a defect in oxidative phosphorylation. LS may be a feature of a deficiency of any of the mitochondrial respiratory chain complexes.[15] [16] [17] [18] [19] [ODPB_HUMAN] Defects in PDHB are the cause of pyruvate dehydrogenase E1-beta deficiency (PDHBD) [MIM:614111]. An enzymatic defect causing primary lactic acidosis in children. It is associated with a broad clinical spectrum ranging from fatal lactic acidosis in the newborn to chronic neurologic dysfunction with structural abnormalities in the central nervous system without systemic acidosis.[20]

Function

[ODPA_HUMAN] The pyruvate dehydrogenase complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links the glycolytic pathway to the tricarboxylic cycle.[21] [22] [ODPB_HUMAN] The pyruvate dehydrogenase complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links the glycolytic pathway to the tricarboxylic cycle.[23] [24]

Publication Abstract from PubMed

The pyruvate dehydrogenase multienzyme complex (PDHc) connects glycolysis to the tricarboxylic acid cycle by producing acetyl-CoA via the decarboxylation of pyruvate. Because of its pivotal role in glucose metabolism, this complex is closely regulated in mammals by reversible phosphorylation, the modulation of which is of interest in treating cancer, diabetes, and obesity. Mutations such as that leading to the alphaV138M variant in pyruvate dehydrogenase, the pyruvate-decarboxylating PDHc E1 component, can result in PDHc deficiency, an inborn error of metabolism that results in an array of symptoms such as lactic acidosis, progressive cognitive and neuromuscular deficits, and even death in infancy or childhood. Here we present an analysis of two X-ray crystal structures at 2.7 A resolution, the first of the disease-associated human alphaV138M E1 variant and the second of human wild-type (WT) E1 with a bound adduct of its coenzyme thiamin diphosphate (ThDP) and the substrate analogue acetylphosphinate (AcPhi). The structures provide support for the role of regulatory loop disorder in E1 inactivation, and the alphaV138M variant structure also reveals that altered coenzyme binding can result in such disorder even in the absence of phosphorylation. Specifically, both E1 phosphorylation at alphaSer264 and the alphaV138M substitution result in disordered loops that are not optimally oriented or available to efficiently bind the lipoyl domain of PDHc E2. Combined with an analysis of alphaV138M activity, these results underscore the general connection between regulatory loop disorder and loss of E1 catalytic efficiency.

Pyruvate dehydrogenase complex deficiency is linked to regulatory loop disorder in the alphaV138M variant of human pyruvate dehydrogenase.,Whitley MJ, Arjunan P, Nemeria NS, Korotchkina LG, Park YH, Patel M, Jordan F, Furey WF J Biol Chem. 2018 Jul 3. pii: RA118.003996. doi: 10.1074/jbc.RA118.003996. PMID:29970614[25]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Ito M, Huq AH, Naito E, Saijo T, Takeda E, Kuroda Y. Mutation of E1 alpha gene in a female patient with pyruvate dehydrogenase deficiency due to rapid degradation of E1 protein. J Inherit Metab Dis. 1992;15(6):848-56. PMID:1338114
  2. ↑ Hansen LL, Brown GK, Kirby DM, Dahl HH. Characterization of the mutations in three patients with pyruvate dehydrogenase E1 alpha deficiency. J Inherit Metab Dis. 1991;14(2):140-51. PMID:1909401
  3. ↑ De Meirleir L, Lissens W, Vamos E, Liebaers I. Pyruvate dehydrogenase (PDH) deficiency caused by a 21-base pair insertion mutation in the E1 alpha subunit. Hum Genet. 1992 Mar;88(6):649-52. PMID:1551669
  4. ↑ Dahl HH, Hansen LL, Brown RM, Danks DM, Rogers JG, Brown GK. X-linked pyruvate dehydrogenase E1 alpha subunit deficiency in heterozygous females: variable manifestation of the same mutation. J Inherit Metab Dis. 1992;15(6):835-47. PMID:1293379
  5. ↑ Chun K, MacKay N, Petrova-Benedict R, Robinson BH. Mutations in the X-linked E1 alpha subunit of pyruvate dehydrogenase leading to deficiency of the pyruvate dehydrogenase complex. Hum Mol Genet. 1993 Apr;2(4):449-54. PMID:8504306
  6. ↑ Matthews PM, Brown RM, Otero LJ, Marchington DR, LeGris M, Howes R, Meadows LS, Shevell M, Scriver CR, Brown GK. Pyruvate dehydrogenase deficiency. Clinical presentation and molecular genetic characterization of five new patients. Brain. 1994 Jun;117 ( Pt 3):435-43. PMID:8032855
  7. ↑ Hansen LL, Horn N, Dahl HH, Kruse TA. Pyruvate dehydrogenase deficiency caused by a 33 base pair duplication in the PDH E1 alpha subunit. Hum Mol Genet. 1994 Jun;3(6):1021-2. PMID:7545958
  8. ↑ Awata H, Endo F, Tanoue A, Kitano A, Matsuda I. Characterization of a point mutation in the pyruvate dehydrogenase E1 alpha gene from two boys with primary lactic acidaemia. J Inherit Metab Dis. 1994;17(2):189-95. PMID:7967473
  9. ↑ Chun K, MacKay N, Petrova-Benedict R, Federico A, Fois A, Cole DE, Robertson E, Robinson BH. Mutations in the X-linked E1 alpha subunit of pyruvate dehydrogenase: exon skipping, insertion of duplicate sequence, and missense mutations leading to the deficiency of the pyruvate dehydrogenase complex. Am J Hum Genet. 1995 Mar;56(3):558-69. PMID:7887409
  10. ↑ Takakubo F, Cartwright P, Hoogenraad N, Thorburn DR, Collins F, Lithgow T, Dahl HH. An amino acid substitution in the pyruvate dehydrogenase E1 alpha gene, affecting mitochondrial import of the precursor protein. Am J Hum Genet. 1995 Oct;57(4):772-80. PMID:7573035
  11. ↑ Hemalatha SG, Kerr DS, Wexler ID, Lusk MM, Kaung M, Du Y, Kolli M, Schelper RL, Patel MS. Pyruvate dehydrogenase complex deficiency due to a point mutation (P188L) within the thiamine pyrophosphate binding loop of the E1 alpha subunit. Hum Mol Genet. 1995 Feb;4(2):315-8. PMID:7757088
  12. ↑ Lissens W, De Meirleir L, Seneca S, Benelli C, Marsac C, Poll-The BT, Briones P, Ruitenbeek W, van Diggelen O, Chaigne D, Ramaekers V, Liebaers I. Mutation analysis of the pyruvate dehydrogenase E1 alpha gene in eight patients with a pyruvate dehydrogenase complex deficiency. Hum Mutat. 1996;7(1):46-51. PMID:8664900 doi:<46::AID-HUMU6>3.0.CO;2-N 10.1002/(SICI)1098-1004(1996)7:1<46::AID-HUMU6>3.0.CO;2-N
  13. ↑ Tripatara A, Kerr DS, Lusk MM, Kolli M, Tan J, Patel MS. Three new mutations of the pyruvate dehydrogenase alpha subunit: a point mutation (M181V), 3 bp deletion (-R282), and 16 bp insertion/frameshift (K358SVS-->TVDQS). Hum Mutat. 1996;8(2):180-2. PMID:8844217 doi:<180::AID-HUMU11>3.0.CO;2-Z 10.1002/(SICI)1098-1004(1996)8:2<180::AID-HUMU11>3.0.CO;2-Z
  14. ↑ Otero LJ, Brown RM, Brown GK. Arginine 302 mutations in the pyruvate dehydrogenase E1alpha subunit gene: identification of further patients and in vitro demonstration of pathogenicity. Hum Mutat. 1998;12(2):114-21. PMID:9671272 doi:<114::AID-HUMU6>3.0.CO;2-# 10.1002/(SICI)1098-1004(1998)12:2<114::AID-HUMU6>3.0.CO;2-#
  15. ↑ Hansen LL, Brown GK, Kirby DM, Dahl HH. Characterization of the mutations in three patients with pyruvate dehydrogenase E1 alpha deficiency. J Inherit Metab Dis. 1991;14(2):140-51. PMID:1909401
  16. ↑ Chun K, MacKay N, Petrova-Benedict R, Federico A, Fois A, Cole DE, Robertson E, Robinson BH. Mutations in the X-linked E1 alpha subunit of pyruvate dehydrogenase: exon skipping, insertion of duplicate sequence, and missense mutations leading to the deficiency of the pyruvate dehydrogenase complex. Am J Hum Genet. 1995 Mar;56(3):558-69. PMID:7887409
  17. ↑ Matthews PM, Marchington DR, Squier M, Land J, Brown RM, Brown GK. Molecular genetic characterization of an X-linked form of Leigh's syndrome. Ann Neurol. 1993 Jun;33(6):652-5. PMID:8498846 doi:http://dx.doi.org/10.1002/ana.410330616
  18. ↑ Dahl HH, Brown GK. Pyruvate dehydrogenase deficiency in a male caused by a point mutation (F205L) in the E1 alpha subunit. Hum Mutat. 1994;3(2):152-5. PMID:8199595 doi:http://dx.doi.org/10.1002/humu.1380030210
  19. ↑ Naito E, Ito M, Yokota I, Saijo T, Matsuda J, Osaka H, Kimura S, Kuroda Y. Biochemical and molecular analysis of an X-linked case of Leigh syndrome associated with thiamin-responsive pyruvate dehydrogenase deficiency. J Inherit Metab Dis. 1997 Aug;20(4):539-48. PMID:9266390
  20. ↑ Brown RM, Head RA, Boubriak II, Leonard JV, Thomas NH, Brown GK. Mutations in the gene for the E1beta subunit: a novel cause of pyruvate dehydrogenase deficiency. Hum Genet. 2004 Jul;115(2):123-7. Epub 2004 May 11. PMID:15138885 doi:10.1007/s00439-004-1124-8
  21. ↑ Korotchkina LG, Patel MS. Mutagenesis studies of the phosphorylation sites of recombinant human pyruvate dehydrogenase. Site-specific regulation. J Biol Chem. 1995 Jun 16;270(24):14297-304. PMID:7782287
  22. ↑ Kato M, Wynn RM, Chuang JL, Tso SC, Machius M, Li J, Chuang DT. Structural basis for inactivation of the human pyruvate dehydrogenase complex by phosphorylation: role of disordered phosphorylation loops. Structure. 2008 Dec 10;16(12):1849-59. PMID:19081061 doi:10.1016/j.str.2008.10.010
  23. ↑ Seifert F, Ciszak E, Korotchkina L, Golbik R, Spinka M, Dominiak P, Sidhu S, Brauer J, Patel MS, Tittmann K. Phosphorylation of serine 264 impedes active site accessibility in the E1 component of the human pyruvate dehydrogenase multienzyme complex. Biochemistry. 2007 May 29;46(21):6277-87. Epub 2007 May 3. PMID:17474719 doi:http://dx.doi.org/10.1021/bi700083z
  24. ↑ Kato M, Wynn RM, Chuang JL, Tso SC, Machius M, Li J, Chuang DT. Structural basis for inactivation of the human pyruvate dehydrogenase complex by phosphorylation: role of disordered phosphorylation loops. Structure. 2008 Dec 10;16(12):1849-59. PMID:19081061 doi:10.1016/j.str.2008.10.010
  25. ↑ Whitley MJ, Arjunan P, Nemeria NS, Korotchkina LG, Park YH, Patel M, Jordan F, Furey WF. Pyruvate dehydrogenase complex deficiency is linked to regulatory loop disorder in the alphaV138M variant of human pyruvate dehydrogenase. J Biol Chem. 2018 Jul 3. pii: RA118.003996. doi: 10.1074/jbc.RA118.003996. PMID:29970614 doi:http://dx.doi.org/10.1074/jbc.RA118.003996

6cer, resolution 2.69Å

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA
Retrieved from "https://proteopedia.openfox.io/wiki/index.php?title=6cer&oldid=3134721"