Name = succinate dehydrogenase complex, subunit B, iron sulfur (Ip)
HGNCid = 10681
Symbol = SDHB
AltSymbols = SDH1, SDH
EntrezGene = 6390
OMIM = 185470
RefSeq = NM_003000
UniProt = P21912
ECnumber = 184.108.40.206
Chromosome = 1
Arm = p
Band = 36.1
LocusSupplementaryData = -p35
SDHB is an acronym for succinate dehydrogenase complex subunit B.
The term SDHB can refer to:
* The protein subunit itself.
* The gene that codes for this protein.
succinate dehydrogenase(SDH) protein complex catalyzes the oxidation of succinate (succinate + ubiquinone => fumarate + ubiquinol). The SDHB subunit is connected to the SDHAsubunit on the hydrophilic, catalytic end of the SDH complex. It is also connected to the SDHC/ SDHDsubunits on the hydrophobic end of the complex anchored in the mitochondrial membrane. The subunit is an iron-sulfur protein with three iron-sulfur clusters. It weighs 30 kDa.
Function of the SDHB protein
The SDH complex is located on the inner membrane of the
mitochondriaand participates in both the Citric Acid Cycleand Respiratory chain.
SDHB acts as an intermediate in the basic SDH enzyme action:
SDHAconverts succinateto fumarateas part of the Citric Acid Cycle. This reaction also converts FADto FADH2.
# Electrons from the FADH2 are transferred to the SDHB subunit iron clusters [2Fe-2S] , [4Fe-4S] , [3Fe-4S] .
# Finally the electrons are transferred to the
Ubiquinone(Q) pool via the SDHC/ SDHDsubunits.This function is part of the Respiratory chain.
Gene that codes for SDHB
The gene that codes for the SDHB protein is nuclear, not mitchondrial DNA. However, the protein is located in the inner membrane of the
mitochondria. The location of the gene in humans is on the first chromosome at p36.1-p35. The geneis coded in 1123 base pairs, partitioned in 8 exons.The expressed protein has 281 amino acids.
Role in Disease
Germlinemutations in the gene can cause familial paraganglioma(in old nomenclature, Paraganglioma Type PGL4). The same condition is often called familial pheochromocytoma.
Tumours related to SDHB mutations have a high rate of malignancy. When malignant, treatment is currently the same as for any malignant paraganglioma/pheochromocytoma.
Tumour and Disease Characteristics
Paragangliomas caused by SDHB mutations have several distinguishing characteristics:
# Malignancy is common, ranging from 38%-83%Neumann, Hartmut P.H. et al. 2004. Distinct Clinical Features of Paraganglioma Syndromes Associated With SDHB and SDHD Gene Mutations."Journal of the American Medical Association". Vol. 292 No. 8. pg. 943- 951.] Brouwers, Frederieke M. et al. 2006. High Frequency of SDHB Germline Mutations in Patients with Maligant Chatecholamine-Producing Paragangliomas: Implications for Genetic Testing ."J Clin Endocrin Metab.".] in carriers with disease. In contrast, tumors caused by
SDHDmutations are almost always benign. Sporadic paragangliomas are malignant in less than 10% of cases.
# Malignant paragangliomas caused by SDHB are usually (perhaps 92%) extra-adrenal. Sporadic pheochromocytomas/paragangliomas are extra-adrenal in less than 10% of cases.
penetranceof the gene is often reported as 77% by age 50 (i.e. 77% of carriers will have at least one tumour by the age of 50). This is likely an overestimate. Currently (2008), families with silent SDHB mutations are being screenedConference: National Insitute of Health (U.S.A.), "SDHB-related Pheochromocytoma: Recent Discoveries & Current Diagnostic and Therapeutic Approaches", September 29, 2006] to determine the frequency of silent carriers.
# The average age of onset is approximately the same for SDHB vs non-SDHB related disease (approximately 36 years).
Mutations causing disease have been seen in
exons 1 through 7, but not 8. As with the SDHCand SDHDgenes, SDHB is a tumor suppressor gene. Note the SDHAgene is not a tumor suppressor gene.
Tumor formation generally follows the Knudson "two hit" hypothesis. The first copy of the gene is mutated in all cells, however the second copy functions normally. When the second copy mutates in a certain cell due to a random event, Loss of Heterozygosity (LOH) occurs and the SDHB protein is no longer produced. Tumor formation then becomes possible.
Given the fundamental nature of the SDH protein in all cellular function, it is not currently understood why only paraganglionic cells are affected. However, the sensitivity of these cells to oxygen levels may play a role.
The precise pathway leading from SDHB mutation to tumorigenesis is not determined; there are several proposed mechanismsGottlieb, Eyal; Tomlinson, Ian P.M. 2005. Mitochondrial Tumor Suppressors: A Genetic and Biochemical Update."Nat. Rev. Cancer". 5(11) pg. 857-866.] .
Pathway 1: Generation of Reactive Oxygen Species
When succinate-ubiquinone activity is inhibited, electrons that would normally transfer through the SDHB subunit to the Ubiquinone pool are instead transferred to O2 to create Reactive Oxygen Species (ROS) such as
superoxide. The dashed red arrow in Figure 2 shows this. ROS accumulate and stabilize the production of HIF1-α. HIF1-α combines with HIF1-β to form the stable HIF heterodimeric complex, in turn leading to the induction of antiapoptotic genes in the cell nucleus.
Pathway 2: Succinate accumulation in the cytosol
SDH inactivation can block the oxidation of
succinate, starting a cascade of reactions:
# The succinate accumulated in the mitochondrial matrix diffuses through the inner and outer mitochondrial membranes to the
cytosol(purple dashed arrows in Figure 2).
# Under normal cellular function,HIF1-α in the cytosol is quickly hydroxylated by
prolyl hydroxylase(PHD), shown with the light blue arrow. This process is blocked by the accumulated succinate.
# HIF1-α stabilizes and passes to the cell nucleus (orange arrow) where it combines with HIF1-β to form an active HIF complex that induces the expression of tumor causing genes Selak, M.A. et al. 2005. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase."Cancer Cell". Vol.7 pg. 77-85.] .
This pathway raises the possibility of a therapeutic treatment. The build-up of succinate inhibits PHD activity. PHD action normally requires oxygen and alpha-ketoglutarate as cosubstrates and ferrous iron and ascorbate as cofactors. Succinate competes with α-ketoglutarate in binding to the PHD enzyme. Therefore, increasing α-ketoglutarate levels can offset the effect of succinate accumulation.
Normal α-ketoglutarate does not permeate cell walls efficiently, and it is necessary to create a cell permeating derivative (e.g. α-ketoglutarate esters). In-vitro trials show this supplementation approach can reduce HIF1-α levels, and may result in a therapeutic approach to tumours resulting from SDH deficiencyMacKenzie, Elaine D. et al. May 2007. Cell-Permeating α-Ketoglutarate Derivatives Alleviate Pseudohypoxia in Succinate Dehydrogenase-Deficient Cells."Molecular and Cellular Biology". Vol.27,No.9 pg. 3282-3289.] .
Pathway 3: Impaired Developmental Apoptosis
Paraganglionic tissue is derived from the
neural crestcells present in an embryo. Abdominal extra-adrenal paraganglionic cells secrete catecholamines that play an important role in fetal development. After birth these cells usually die, a process that is triggered by a decline in nerve growth factor(NGF)which initiates apoptosis(cell death).
This cell death process is mediated by an enzyme called prolyl hydroxylase EglN3. Succinate accumulation caused by SDH inactivation inhibits the prolyl hydroxylase EglN3Lee S., Nakamura E., et al. August 2005. Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer."Cancer Cell". Vol.8,pg. 155-167.] ..
The net result is that paranglionic tissue that would normally die after birth remains, and this tissue may be able to trigger paraganglioma/pheochromocytoma later.
Pathway 4: Glycolysis upregulation
Inhibition of the Citric Acid Cycle forces the cell to generate ATP glycolytically in order to generate its required energy. The induced glycolytic enzymes could potentially block cell apoptosis.
* [http://chromium.liacs.nl/lovd_sdh/index.php?select_db=SDHB Database of identified mutations.]
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