Preferred Label : The Citric Acid Cycle;
NCIt synonyms : The Krebs Cycle; Szent-Gyorgyi-Krebs Cycle; TCA Cycle; Tricarboxylic Acid Cycle;
Alternative definition : BIOCARTA: The Krebs cycle, also called the citric acid cycle, is a fundamental metabolic
pathway involving eight enzymes essential for energy production through aerobic respiration,
and, like glycolysis, arose early in evolution. This pathway is also an important
source of biosynthetic building blocks used in gluconeogenesis, amino acid biosynthesis,
and fatty acid biosynthesis. The Krebs cycle takes place in mitochondria where it
oxidizes acetyl-CoA, releasing carbon dioxide and extracting energy primarily as the
reduced high-energy electron carriers NADH and FADH2. NADH and FADH2 transfer chemical
energy from metabolic intermediates to the electron transport chain to create a different
form of energy, a gradient of protons across the inner mitochondrial membrane. The
energy of the proton gradient in turn drives synthesis of the high-energy phosphate
bonds in ATP, the common energy currency of the cell used to drive a huge variety
of reactions and processes. An acetyl-CoA molecule (2 carbons) enters the cycle when
citrate synthase condenses it with oxaloacetate (4 carbons) to create citrate (6 carbons).
One source of the acetyl-CoA that enters the Krebs cycle is the conversion of pyruvate
from glycolysis to acetyl-CoA by pyruvate dehydrogenase. Acetyl-CoA is a key metabolic
junction, derived not only from glycolysis but also from the oxidation of fatty acids.
As the cycle proceeds, the Krebs cycle intermediates are oxidized, transferring their
energy to create reduced NADH and FADH2. The oxidation of the metabolic intermediates
of the pathway also releases two carbon dioxide molecules for each acetyl-CoA that
enters the cycle, leaving the net carbons the same with each turn of the cycle. This
carbon dioxide, along with more released by pyruvate dehydrogenase, is the source
of CO2 released into the atmosphere when you breathe. The Krebs cycle, like other
metabolic pathways, is tightly regulated to efficiently meet the needs of the cell
and the organism. The irreversible synthesis of acetyl-CoA from pyruvate by pyruvate
dehydrogenase is one important regulatory step, and is inhibited by high concentrations
of ATP that indicate abundant energy. Citrate synthase, alpha-ketoglutarate dehydrogenase
and isocitrate dehydrogenase are all key regulatory steps in the cycle and are each
inhibited by abundant energy in the cell, indicated through high concentrations of
ATP or NADH. The activity of the Krebs cycle is closely linked to the availability
of oxygen, although none of the steps in the pathway directly use oxygen. Oxygen is
required for the electron transport chain to function, which recycles NADH back to
NAD and FADH2 back to FADH, providing NAD and ADH required by enzymes in the Krebs
cycle. If the oxygen supply to a muscle cell or a yeast cell is low, NAD and FADH
levels fall, the Krebs cycle cannot proceed forward, and the cell must resort to fermentation
to continue making ATP. Some Krebs cycle enzymes require non-protein cofactors for
activity, such as thiamine, vitamin B1. Insufficient quantities of this vitamin in
the diet leads to decreased activity of pyruvate dehydrogenase and alpha-ketoglutarate
dehydrogenase, and a decrease in the ability of the Krebs cycle to meet metabolic
demands, causing the disease beriberi. Although the elucidation of the Krebs cycle
remains one of the landmarks of biochemistry, aspects of the Krebs cycle and its enzymes
are still actively researched in the modern proteomic era. (This definition may be
outdated - see the DesignNote.);
NCIt note : The BIOCARTA Definition (ALT_DEFINITION) for this pathway concept was provided by
BioCarta. This property was not created by, nor is it maintained by the NCI Thesaurus
staff. Additionally, BioCarta is no longer updating its pathway data; thus, the BIOCARTA
Definition might be outdated or inaccurate. Please see the Terms and Conditions for
Use at http://www.biocarta.com/.;
NCI Metathesaurus CUI : CL422155;
Biocarta ID : krebPathway;
Origin ID : C91329;
UMLS CUI : C0008858;
Currated CISMeF NLP mapping
- Semantic type(s)
- UMLS correspondences (same concept)
- has_gene_product_element
- pathway_has_gene_element
