.6. In patients with whooping cough, Gαi is inhibited. How does this lead to a rise in cyclic adenosine monophosphate (cAMP)?
G proteins of the Gαi type inhibit adenylyl cyclase (AC) when their associated G protein–coupled receptor is bound by ligand. If Gαi is inhibited by pertussis toxin, AC production of cAMP is inappropriately activated.
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I. CYCLE OVERVIEW
The tricarboxylic acid cycle ([TCA cycle] also called the citric acid cycle, or the Krebs cycle) plays several roles in metabolism. It is the final pathway where the oxidative catabolism of carbohydrates, amino acids, and fatty acids converge, their carbon skeletons being converted to carbon dioxide (CO2), as shown in cycle. The TCA cycle is an aerobic pathway, because oxygen (O2) is required as the final electron acceptor. Reactions such as the catabolism of some amino acids generate intermediates of the cycle and are called anaplerotic (from the Greek for “filling up”) reactions. The TCA cycle also provides intermediates for a number of important anabolic reactions, such as glucose formation from the carbon skeletons of some amino acids and the synthesis of some amino acids (see p. 267) and heme (see p. 278). Therefore, this cycle should not be viewed as a closed system but, instead, as an open one with compounds entering and leaving as required.
II. CYCLE REACTIONS
In the TCA cycle, oxaloacetate (OAA) is first condensed with an acetyl group from acetyl coenzyme A (CoA) and then is regenerated as the cycle is completed (see Fig. 9.1). Two carbons enter the cycle as acetyl CoA and two leave as CO2.
Therefore, the entry of one acetyl CoA into one round of the TCA cycle does not lead to the net production or consumption of intermediates.
A. Acetyl CoA production
The major source of acetyl CoA for the TCA cycle is the oxidative decarboxylation of pyruvate by the multienzyme pyruvate dehydrogenase complex (PDH complex, or PDHC). However, the PDHC (described below) is not a component of the TCA cycle. Pyruvate, the end product of aerobic glycolysis, is transported from the cytosol into the mitochondrial matrix by the pyruvate mitochondrial carrier of the inner mitochondrial membrane. In the matrix, the PDHC converts pyruvate to acetyl CoA. [Note: Fatty acid oxidation is another source of acetyl CoA (see p. 192).] 1. PDHC component enzymes: The PDHC is a protein aggregate of multiple copies of three enzymes, pyruvate decarboxylase ([E1] sometimes called pyruvate dehydrogenase), dihydrolipoyl transacetylase (E2), and dihydrolipoyl dehydrogenase (E3). Each catalyzes a part of the overall reaction (Fig. 9.2). Their physical association links the reactions in proper sequence without the release of intermediates. In addition to the enzymes participating in the conversion of pyruvate to acetyl CoA, the PDHC also contains two regulatory enzymes, pyruvate dehydrogenase kinase (PDH kinase) and pyruvate dehydrogenase phosphatase (PDH phosphatase).
dioxide; TPP = thiamine pyrophosphate; L = lipoic acid; CoA = coenzyme A; FAD(H2) and NAD(H) = flavin and nicotinamide adenine dinucleotides; ~ = high-energy bond.