Respiratory chain biosynthesis

Mitochondria are also described as being the cell s biochemical powerhouse, since—through oxidative phosphorylation (see p. 112)—they produce the majority of cellular ATP. Pyruvate dehydrogenase (PDH), the tricarboxylic acid cycle, p-oxidation of fatty acids, and parts of the urea cycle are located in the matrix. The respiratory chain, ATP synthesis, and enzymes involved in heme biosynthesis (see p. 192) are associated with the inner membrane. 

Within the past few years, there has been considerable progress in understanding the role played by the mitochondria in the cellular homeostasis of iron. Thus, erythroid cells devoid of mitochondria do not accumulate iron (7, 8), and inhibitors of the mitochondrial respiratory chain completely inhibit iron uptake (8) and heme biosynthesis (9) by reticulocytes. Furthermore, the enzyme ferrochelatase (protoheme ferro-lyase, EC 4.99.1.1) which catalyzes the insertion of Fe(II) into porphyrins, appears to be mainly a mitochondrial enzyme (10,11,12,13, 14) confined to the inner membrane (15, 16, 17). Finally, the importance of mitochondria in the intracellular metabolism of iron is also evident from the fact that in disorders with deranged heme biosynthesis, the mitochondria are heavily loaded with iron (see Mitochondrial Iron Pool, below). It would therefore be expected that mitochondria, of all mammalian cells, should be able to accumulate iron from the cytosol. From the permeability characteristics of the mitochondrial inner membrane (18) a specialized transport system analogous to that of the other multivalent cations (for review, see Ref. 19) may be expected. The relatively slow development of this field of study, however, mainly reflects the difficulties in studying the chemistry of iron. 

DHODs are FMN-containing enzymes that convert dihydroorotate (DHO) to orotate (OA) in the only redox step in the wow synthesis of pyrimidines (Scheme 12). DHODs have been grouped into two classes based on sequence. Class 2 DHODs are membrane-bound monomers that are reoxidized by ubiquinone, coupling pyrimidine biosynthesis to the respiratory chain. On the other hand, Class 1 DHODs are cytosolic proteins that have been further divided into two subclasses. Class lA DHODs are homodimers that are reoxidized by fumarate. Class 1B DHODs are azfiz heterotetramers with an FMN-containing subunit very similar to Class 1A enzymes and a second subunit that contains an iron—sulfur cluster and FAD, allowing Class IB DHODs to be reoxidized by NAD. ... 

PG is made in mitochondria and microsomes of animal cells and appears to be primarily converted to DPG. DPG is biosynthesized exclusively on the matrix side of the mitochondrial inner membrane and is found only in this organelle. There is evidence that the rate-limiting step in DPG biosynthesis is the conversion of PA into CDP-DG (G.M. Hatch, 1994). Consistent with this idea, the levels of CTP regulate DPG biosynthesis in cardiac myoblasts (G.M. Hatch, 1996). Using techniques developed by Raetz and co-workers [14], a temperature-sensitive mutant of PG-P synthase in CHO cells was isolated (M. Nishijima 1993). The mutant had only 1% of wild-type PG-P synthase activity at 40°C and exhibited a temperature-sensitive defect in PG and DPG biosynthesis. This mutant was used to show that DPG is required for the NADH-ubiquinone reductase (complex I) activity of the respiratory chain. 

Voltage gated sodium channel (vgSCh) y-aminobutyric add (GABA) receptor/chloride ionophore complex chitin biosynthesis pathways mitochondrial respiratory chain and ryanodine receptor for insedicides. 

Sterol biosynthesis mitochondrial respiratory chain germination and hyphal growth protein kinase for fungicides. 

Since trimethylbenzoquinone is not converted into 2 , it appears that the complete side chain of a-tocopherol is not removed before building up the Cso side chain. In this respect, the biosynthesis of 2 differs from that of vitamin K2 The possible biochemical significance of 2 , which we can also think of as deoxyubiquinone, in the mitochondrial respiratory chain remains to be investigated. It would obviously be of great interest if this new compound is found to be present in mitochondria. Ubiquinone and tocopherol are present, but tocopherylquinonc is not. If the new vitamin compound were found in mitochondria, it would clearly support those who would ascribe to vitamin some specific function in respiratory-enzyme systems. This possibility has existed ever since the... 

The biosynthesis of ATP involves the flow of both electrons (e ) and protons (H ) in the respiratory chain to form ATP by the process known as oxidative phosphorylation. The respiratory chain comprises four structures known as complex I, complex II, complex III and complex IV and a mushroom-shaped structure (ATP synthetase alias Fq/Fi or complex V) that synthesises ATP from ADP and inorganic phosphate (Pi). We will consider the flow of electrons and protons (i) first from complex I, and (ii) from complex II. 

Krebs cycle has different functions in different tissues. For example, in muscle and brain it oxidises acetyl CoA to form NADH and FADH2, which are used to generate ATP in the respiratory chain (Chapters 11-13). In liver, during fasting, acetyl CoA is not oxidised by Krebs cycle. Instead, sections of Krebs cycle operate to direct amino acid derivatives towards malate for gluconeogenesis (Chapter 46). In liver and adipose tissue, after feeding, the destiny of acetyl CoA is a brief sojourn in Krebs cycle by incorporation into citrate before export to the cytosol for biosynthesis to fatty acids (Chapter 21). 

Other examples of M.c. are anthranilate synthase and tryptophan synthase, which are involved in microbial Aromatic biosynthesis (see), and citrate lyase. The definition of M. c. may be extended to include the membrane-bound respiratory chain, the contractile protein complexes of muscle, and the ribosome (which also contains RNA), etc. 

Pyruvate dehydrogenase (PDH) is located at a key junction point in sugar metabolism between the glycolysis and the tricarboxylic acid (TCA) cycle (Patel and Roche 1990). It catalyses the irreversible conversion of pyruvate, CoA and NAD into CO2, NADH and acetyl-CoA. Acetyl-CoA serves as a precursor for the TCA cycle and the biosynthesis of fatty acids and steroids, and NADH provides the reducing equivalents into the respiratory chain for oxidative phosphorylation. 

---