DEFINITION
The enzyme citrate synthase, CISY E.C. 2.3.3.1 exists in nearly all living cells and stands as a pace-making enzyme in the first step of the citric acid cycle (or Krebs cycle). Citrate synthase is localized within eukaryotic cells in the mitochondrial matrix, but is encoded by nuclear DNA rather than mitochondrial. It is synthesized using cytoplasmic ribosomes, then transported into the mitochondrial matrix
The enzyme ATP citrate lyase, ACLY E.C. 2.3.3.8 is a cytoplasmic enzyme that in animals represents an important step in biosynthetic pathways requiring Acetyl-CoA.
The enzyme links carbohydrate metabolism, which yields citrate as an intermediate, with pathways like fatty acid biosynthesis, which consumes acetyl-CoA.
TXTP is required to exchange citrate/malate
THE GENE
CHEMICAL STRUCTURE AND IMAGES
When relevant to the function
- Primary structure
- Secondary structure
- Tertiary structure
- Quaternary structure
Protein Aminoacids Percentage (Width 700 px)
Glu/Gln typical of partially oxygenated tissues (TXTP is the more ancient), met higher in CISY/ACLY, Trp low = low proliferation, Gly high in CISY/ACLY
The more interesting observation is that, from the evolutionary point of view, the sequence is TXTP --> CISY --> ACLY --> MORC2
SYNTHESIS AND TURNOVER
mRNA synthesis
protein synthesis
Citrate synthase CISY is commonly used as a quantitative enzyme marker for the presence of intact mitochondria. The maximal activity of citrate synthase indicates the mitochondrial content of skeletal muscle. The maximal activity can be increased by endurance training or high-intensity interval training.
post-translational modifications
degradation
CELLULAR FUNCTIONS
cellular localization,
biological function
- Cell signaling and Ligand transport
- Structural proteins
REGULATION
The enzyme CISY is inhibited by high ratios of ATP:ADP and NADH:NAD, as high concentrations of ATP and NADH show that the energy supply is high for the cell. It is also inhibited by succinyl-CoA and propionyl-CoA, which resembles Acetyl-coA and acts as a competitive inhibitor to acetyl-CoA and a noncompetitive inhibitor to oxaloacetate. Citrate inhibits the reaction and is an example of product inhibition. The inhibition of citrate synthase by acetyl-CoA analogues has also been well documented and has been used to prove the existence of a single active site.
Inhibitors
Bempedoic acid is an oral, once-daily, small molecule with a half-life of 15–24 h. It is responsible for the inhibition of ATP citrate lyase (ACLY), a cytosolic enzyme upstream of HMG-CoA reductase, and therefore used for lowering serum cholesterol...
DIAGNOSTIC USE
