Cellular Respiration

Cellular respiration is a process where typically, glucose is catabolized in a series of steps for the sake of producing ATP. Respiratory pathways interact with amino acid, nucleic acid, carbohydrate, and lipid anabolic/catabolic pathways. In eukaryotes, aerobic respiration typically occurs in the mitochondria (the Krebs cycle occurs in the mitochondrial matrix, and the electron transport chain is found on the inner mitochondrial membrane). In prokaryotes, cellular respiration occurs on the cell membrane.

Respiration can be anaerobic, aerobic, or fermentative. Anaerobic respiration uses an inorganic molecule as the final electron acceptor. Aerobic respiration uses $\text{O}_2$ as the final electron acceptor. Fermentation uses an organic molecule as the final electron acceptor.

Glycolysis is a very common pathway used to split glucose. Glycolysis always happens in the cytoplasm.

First, hexokinase adds a phosphate group from ATP to glucose. Because phosphate is negatively charged, the glucose 6-phosphate is now trapped in the cell. Glucose-6 phosphate is then converted into its isomer via phosphoglucoisomerase into fructose 6-phosphate. Phosphofructokinase adds a second phosphate group using ATP to fructose-6 phosphate, resulting fructose 1, 6-bisphosphate. This is a key regulatory step of glycolysis. Then, aldolase cleaves fructose 1, 6-bisphosphate into two three-carbon sugars, dihydroxyacetone phosphate and glyceraldehyde 3-phosphate. Isomerase converts dihydroxyacetone phosphate into glyceraldehyde 3-phosphate, which can continue in the glycolytic pathway. Each glyceraldehyde 3-phosphate is then oxidized by triose phosphate dehydrogenase, and the electrons are used to reduce nicotinamide adenine dinucleotide (NAD+) into NADH. The result is 1, 3-bisphosphoglycerate. Then, substrate level phosphorylation occurs, where phosphate is taken from each 1, 3-3 bisphosphoglycerate via phosphoglycerokinase (don't forget that there are two of them due to the split of the 6-carbon sugar) and added to ADP to form ATP. The result is 3-phosphoglycerate. Phosphoglyceromutase moves the phosphate group from the oxygen of the 3-carbon to the oxygen on the 2-carbon, resulting in 2-phosphoglycerate. Enolase takes out a water form 2-phosphoglycerate, yielding phosphoenolpyruvate, a very important molecule. Finally, pyruvate kinase catalyzes substrate-level phosphorylation, yielding ATP and pyruvate.

Summary of glycolysis:

Input: Glucose, 2 ATP, 2 NAD+

Output: 4 ATP, 2 NADH, 2 pyruvate

If the cell is able to do aerobic respiration, then the pyruvate will undergo oxidative decarboxylation. Via the pyruvate dehydrogenase complex, CoA-SH is added onto pyruvate, NAD+ oxidizes pyruvate, and as a result, $CO_{2}$, NADH, and Acetyl-CoA are released. It's important to note that pyruvate is a 3-carbon molecule while Acetyl-CoA is a 2-carbon molecule.

Acetyl-CoA then continues into the Krebs Cycle, which occurs in the mitochondrial matrix in eukaryotes, and in the cytoplasm in prokaryotes. First, acetyl CoA is combined with oxaloacetate, a 4-carbon molecule, into citrate, a 6-carbon molecule via citrate synthase and through the addition of water. Acontase converts citrate into its isomer, isocitrate. Then, isocitrate dehydrogenase oxidizes isocitrate into α-ketoglutarate; this reduces an NAD+ using electrons from isocitrate and releases a $CO_{2}$ molecule. Notice that α-ketoglutarate is a 5-carbon molecule. α-ketoglutarate is again oxidized by α-ketoglutarate dehydrogenase into succinyl-CoA, a 4-carbon molecule. In this reaction, another NAD+ is reduced by using electrons from α-ketoglutarate, CoA-SH is added onto α-ketoglutarate, and $CO_{2}$ is released. Succinyl-CoA is converted into succinate via succinyl-CoA synthetase, which releases the CoA-SH and converts GDP into GTP. Succinate is then converted into fumarate via succinate dehydrogenase, which uses electrons in fumarate to reduce FAD into $FADH_{2}$. Fumarase adds water into fumarate to generate malate. Malate dehydrogenase uses electrons from malate to reduce NAD+ into NADH, generating oxaloacetate. We are now back at the "beginning" of the Krebs cycle. Note that for each glucose, the Krebs cycle turns twice.

In order to continue respiration, whether it's glycolysis or the Krebs cycle, we need more NAD+. The electron transport chain helps regenerate NAD+. There are carrier complexes embedded in the inner mitochondrial membrane that oxidize NADH back into NAD+ (and one carrier complex oxidizes $FADH_{2}$ back into FAD). The NADH dehydrogenase complex accepts electrons from NADH, and the Q complex accepts electrons from $FADH_{2}$. These complexes use the electrons gained from those coenzymes to power the pumping of protons $(H^+ )$ from the mitochondrial matrix across the inner mitochondrial membrane into the intermembrane space. This creates a concentration gradient, with a higher proton concentration in the intermembrane space than in the mitochondrial matrix. The protons then flow back into the mitochondrial matrix through ATP synthase. As the protons flow through ATP synthase, ATP synthase spins. This proton motive force provides energy for ATP synthase to attach inorganic phosphate to ADP, producing ATP. This process is also an example chemioosmosis, or when energy stored by a proton gradient is utilized to do cell work. After the electron energy is "used up" by the previous electron carrier complexes, the electrons and two protons combine with oxygen, the final electron acceptor/ to make water via the cytochrome oxidase complex.

(To be continued)

Glucose isn't the only compound used in respiration. Amino acids can be converted into pyruvate and acetyl CoA, and can thus enter into the respiratory pathway in glycolysis and the Krebs cycle, respectively. Multiple carbohydrates can be used (such as fructose), provided that they're converted into forms that can enter glycolysis (such as fructose-6 phosphate). Lipids can be broken down into glycerol, and fatty acids; the glycerol can be converted into glyceraldehyde 3-phosphate and enter glycolysis, and the fatty acids can be broken down into two-carbon molecules through β-oxidation, and enter the Krebs cycle as acetyl CoA.

In anaerobic respiration, the final electron acceptor is an inorganic molecule, such as sulfate, nitrate, iron ions, etc.

Some bacteria use the pentose phosphate shunt in conjunction with glycolysis. The pentose phosphate shunt uses glucose-6 phosphate and can produce pentose sugars that are used in nucleotide synthesis, and also leads to synthesis of glycolysis intermediates glyceraldehyde 3-phosphate and fructose 6-phosphate.

Other bacteria may use the Entner-Doudoroff pathway, which is separate from glycolysis. It's a similar pathway, as it produces pyruvate and ATP from glucose, but it also produces NADPH in addition to NADH, and it utilizes different enzymes not found in glycolysis.