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SDHB is an acronym for succinate dehydrogenase complex subunit B.
The term SDHB can refer to:
The succinate dehydrogenase (SDH) protein complex catalyzes the oxidation of succinate (succinate + ubiquinone => fumarate + ubiquinol). The SDHB subunit is connected to the SDHA subunit on the hydrophilic, catalytic end of the SDH complex. It is also connected to the SDHC/SDHD subunits 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.
Additional recommended knowledge
Function of the SDHB protein
SDHB acts as an intermediate in the basic SDH enzyme action:
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 gene is coded in 1123 base pairs, partitioned in 8 exons. The expressed protein has 281 amino acids.
Role in Disease
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:
The precise pathway leading from SDHB mutation to tumorigenesis is not determined; there are several proposed mechanisms.
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:
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 deficiency.
Pathway 3: Impaired Developmental Apoptosis
Paraganglionic tissue is derived from the neural crest cells 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 EglN3..
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.
|This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "SDHB". A list of authors is available in Wikipedia.|