SDHB

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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.

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.

[edit] Function of the SDHB protein

Figure 1: Function of the SDHB protein. Electrons are transferred from the Citric Acid Cycle to the Respiratory Chain. Electron path is shown by red arrows.

The SDH complex is located on the inner membrane of the mitochondria and participates in both the Citric Acid Cycle and Respiratory chain.

SDHB acts as an intermediate in the basic SDH enzyme action:

1. SDHA converts succinate to fumarate as part of the Citric Acid Cycle. This reaction also converts FAD to FADH₂.
2. Electrons from the FADH₂ are transferred to the SDHB subunit iron clusters [2Fe-2S],[4Fe-4S],[3Fe-4S].
3. Finally the electrons are transferred to the Ubiquinone (Q) pool via the SDHC/SDHD subunits.This function is part of the Respiratory chain.

[edit] Gene that codes for SDHB

The gene that codes for the SDHB protein is nuclear, not mitchondrial DNA even though 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.

[edit] Role in Disease

Germline mutations in the gene can cause familial pheochromocytoma (also called familial paraganglioma type PGL4). Mutations causing disease have been seen in exons 1 through 7, but not 8. As with the other SDH genes, SDHB is a tumor suppressor gene.

Tumorigenesis follows the Knudson "two hit" hypothesis, and so tumour suppressor inactivation usually (but not always) leads to loss of heterozygosity in tumour cells.

[edit] Tumour and Disease Characteristics

Paraganglioma caused by SDHB mutations have several distinguishing characteristics:

1. Malignancy is common, ranging from 38%-83%^[1][2] in carriers with disease. In contrast, sporadic paragangliomas are malignant in less than 10% of cases. Note that tumours caused by SDHD mutations are almost always benign.
2. Malignant paragangliomas caused by SDHB are usually (perhaps 92%^[2]) extra-adrenal. In contrast, sporadic pheochromocytomas/paragangliomas are extra-adrenal in less than 10% of cases.
3. The penetrance of the gene is often reported as 77% by age 50^[1] (i.e. 77% of carriers will have at least one tumour by the age of 50). This is almost certainly an overestimate. As of January, 2007 many families carrying the gene are being screened, and there are many carriers not exhibiting disease.
4. Oddly, the average age of onset is the same for SDHB vs non-SDHB caused disease (approximately 36 years).

[edit] Disease pathways

The precise pathway leading from SDHB mutation to tumorigenesis is not determined; there are several proposed mechanisms^[3].

[edit] Pathway 1: generation of Reactive Oxygen Species

Figure 2:Disease Pathways for SDHB mutations. Electron path during normal function is shown by solid red arrows. Red dashed arrow shows superoxide generation (Pathway 1). Purple dashed arrow shows diffusion of succinate to block PHD (Pathway 2). Black crosses indicate the non-mutated process is blocked.

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 the figure shows this. Reactive Oxygen Species (ROS) accumulates and stabilizes the production of HIF1-α. HIF-α combines with HIF-β to form the stable HIF heterodimeric complex, in turn leading to the induction of antiapoptotic genes in the cell nucleus.

[edit] Pathway 2: Succinate accumulation in the cytosol

SDH inactivation can block the oxidation of succinate, starting a cascade of reactions:

1. The succinate accumulated in the mitochondrial matrix diffuses through the inner and outer mitochondrial membranes to the cytosol (purple dashed arrows in Figure 2).
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.
3. HIF1-α stabilizes and passes to the cell nucleus (orange arrow) where it forms an active HIF complex (along with HIF1-β) that induces the expression of tumor causing genes ^[4].

[edit] Pathway 3: 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.

[edit] References