Pyruvate/citrate shuttle

In animals and fungi there is a similar dichotomy. NADPH can be generated by cytosolic malic enzyme which catalyses the reaction malate + NADP+ — pyruvate + COg + NADPH. Cytosolic malate derives from the following successive reactions the pyruvate/ citrate shuttle on the mitochondrial inner membrane takes pyruvate to the mitochondrion in exchange for citrate cytosolic ATP citrate lyase catalyses ATP + citrate + CoA-SH —> acetylCoA (CH3CO-S-C0A) + oxaloacetate and cytosolic malate dehydrogenase, which catalyses NADH + oxaloacetate NAD+ + malate. This scheme provides both acetylCoA and NADPH for subsequent long chain fatty acid synthesis (see section on Fatty acid synthesis ). 

FIGURE 25.1 The citrate-malate-pyruvate shuttle provides cytosolic acetate units and reducing equivalents (electrons) for fatty acid synthesis. The shuttle collects carbon substrates, primarily from glycolysis but also from fatty acid oxidation and amino acid catabolism. Most of the reducing equivalents are glycolytic in origin. Pathways that provide carbon for fatty acid synthesis are shown in blue pathways that supply electrons for fatty acid synthesis are shown in red. 

FIGURE 21-10 Shuttle for transfer of acetyl groups from mitochondria to the cytosol. The mitochondrial outer membrane is freely permeable to all these compounds. Pyruvate derived from amino acid catabolism in the mitochondrial matrix, or from glucose by glycolysis in the cytosol, is converted to acetyl-CoA in the matrix. Acetyl groups pass out of the mitochondrion as citrate in the cytosol they are de-... 

Fatty acids are generated cytoplasmically while acetyl-CoA is made in the mitochondrion by pyruvate dehydrogenase.This implies that a shuttle system must exist to get the acetyl-CoA or its equivalent out of the mitochondrion. The shuttle system operates in the following way Acetyl-CoA is first converted to citrate by citrate synthase in the TCA-cycle reaction. Then citrate is transferred out of the mitochondrion by either of two carriers, driven by the electroos-motic gradient either a citrate/phosphate antiport or a citrate/malate antiport as shown in Figure 2-2. 

VDAC plays a role in the regulated flux of metabolites—usually anionic species such as phosphate, chloride, organic anions, and the adenine nucleotides—across the outer membrane. VDAC appears to form an open p -barrel structure similar to that of the bacterial porins (Section 12.5.2). although mitochondrial porins and bacterial porins may have evolved independently. Some cytoplasmic kinases bind to VDAC, thereby obtaining preferential access to the exported ATP. In contrast, the inner membrane is intrinsically impermeable to nearly all ions and polar molecules. A large family of transporters shuttles metabolites such as ATP, pyruvate, and citrate across the inner mitochondrial membrane. The two faces of this membrane will be referred to as the matrix side and the cytosolic side (the latter because it is freely accessible to most small molecules in the cytosol). They are also called the N and P sides, respectively, because the membrane potential is negative on the matrix side and positive on the cytosolic side. 

The noncompartmented model consisted of 73 transformers (reaction rates and transport step), balancing 53 metaboHtes. The compartmented approach was buUt on 95 transformers and 75 metabolites. While most of the simulated fluxes were similar in both approaches, a fraction of approximately 15% of totally available ATP was missing in the compartmented model compared to the noncompartmented approach. This was due to the assumed activity of the citrate-pyruvate shuttle that imports pyruvate (via pyruvate/H+ symporter) into mitochondria by exporting citrate (via citrate/malate antiporter). In cytoplasm, citrate is further... 

Oxaloacetate is an intermediate of many metabolic pathways. It also plays a role in the malate-aspartate shuttle, which transfers high energy electrons into mitochondria. Citrate is formed by the condensation of oxaloacetate with acetyl CoA. A transamination reaction transfers an amino group from an amino acid to an a-keto acid. Transfer of the amino group from aspartate to a-ketoglutarate forms oxaloacetate and glutamate. In gluconeogenesis, pyruvate is carboxylated in mitochondria to form oxaloacetate. After transfer to the cytosol, the enzyme phosphoenolpyruvate carboxykinase catalyses the conversion of oxaloacetate to phosphoenolpyruvate. 

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