Endoplasmic Reticulum: Protein Synthesis, Lipid Metabolism, and Detoxification
Endoplasmic Reticulum Functions
Protein Synthesis (Rough ER)
The rough endoplasmic reticulum (RER) is crucial for the synthesis of proteins destined for export from the cell or for delivery to other intracellular locations. This process begins with free ribosomes in the hyaloplasm. The key difference between mRNA for exportable proteins and non-exportable proteins lies in the signal hypothesis.
The mRNA of exportable proteins contains a series of signal codons immediately after the start codon (AUG). These initial codons indicate whether the protein should be exported. The mRNA binds to the small ribosomal subunit, forming the initiation complex, and then binds to the large subunit to initiate protein synthesis.
If the protein is exportable, the signal peptide emerges from the ribosome. A signal recognition particle (SRP), composed of six chains and RNA, binds to the ribosome at one end and to the signal peptide at the other, blocking synthesis until the polysome chain attaches to the ER. The interaction between the SRP and its receptor depends on GTP. Exportable protein synthesis then occurs within the RER.
Lipid Synthesis and Metabolism (Smooth ER)
The smooth endoplasmic reticulum (SER) is the primary site for lipid synthesis and metabolism, with the exception of some fatty acids and phospholipids synthesized in the mitochondria. The SER is involved in the synthesis of phospholipids, phosphoglycerides, cholesterol, cholesterol derivatives, and steroid hormones.
Cholesterol is used to produce pregnenolone, an intermediate molecule that remains in the REL membrane. Inside the membrane, it undergoes hydroxylations to become intermediates in the synthesis of estrogen, androgen, and progesterone. Alternatively, it can be converted into another metabolite that returns to the mitochondria to become cortisol or aldosterone.
Other Functions of the Smooth ER
- Elongation and Desaturation of Fatty Acids: The SER plays a role in these processes.
- Calcium Storage: In muscle cells, the SER stores calcium ions (Ca2+). ATPases in the SER membranes regulate calcium levels, releasing Ca2+ at specific stages of muscle contraction.
- Glycogen Metabolism: In the liver, the SER is involved in glycogen metabolism. Glycogen is stored in the cytoplasm of hepatocytes.
- Detoxification: The SER plays a critical role in detoxification.
Glycosylation
Glycosylation involves the addition of sugars to lipids and proteins synthesized in the ER, facilitated by glycosyltransferases. This modification is important for protein stability, solubility, charge, and recognition.
Detoxification
The ER membrane metabolizes toxic substances encountered in the stomach and intestine, transforming them into less toxic forms. This process involves two main types of reactions:
Oxidation
Oxidation inactivates toxic substances using oxygen (O2) and cytochrome P-450 with its reductase, leading to the oxidation of the toxic substance.
Conjugation
Conjugation involves the addition of glucuronic acid to inactivate the toxic substance. This can occur directly or as a result of oxidation.
ER Biogenesis
New ER cisternae are formed through the synthesis of proteins. External peripheral proteins are synthesized in polysomes, while internal peripheral proteins are synthesized in ribosomes. Proteins within the endoplasmic reticulum that are glycosylated require proper folding. If they do not bind to chaperones (calnexin, calreticulin), they are exported to the hyaloplasm and degraded.