Question

Assume that acetyl CoA containing a \(14 \mathrm{C}\) isotopic label in the carboxyl carbon atom is used as starting material and that the mevalonate pathway is followed. Identify the positions in lanosterol where the label would appear.

Short answer

No positions in lanosterol are labeled with 14C.

Step-by-step solution

Understand the Mevalonate Pathway

The mevalonate pathway is a crucial metabolic pathway that converts acetyl-CoA into isoprenoids, including sterols like lanosterol. The pathway involves a series of enzymatic reactions that lead from acetyl-CoA to mevalonate, then to isopentenyl pyrophosphate (IPP), and ultimately to complex terpenoids and sterols.

Start with Acetyl-CoA

Acetyl-CoA is used as the starting material in the mevalonate pathway. The acetyl group consists of two carbon atoms: the methyl carbon and the carboxyl carbon. In this exercise, the carboxyl carbon is labeled with the radioactive isotope 14C.

Follow the Carbon to Mevalonate

During the conversion to mevalonate, three acetyl-CoA molecules are condensed into eta-hydroxy-eta-methylglutaryl-CoA (HMG-CoA), and then reduced to form mevalonate. The labeled carboxyl carbon from one acetyl-CoA becomes one of the carboxyl groups in mevalonate.

Conversion to Isopentenyl Pyrophosphate (IPP)

Mevalonate is then phosphorylated and decarboxylated to produce isopentenyl pyrophosphate (IPP), a five-carbon building block. The 14C label, originally located in the carboxyl group, is lost as CO2 during the decarboxylation step and is not in IPP.

Synthesis of Farnesyl Pyrophosphate (FPP)

IPP units are combined to form larger intermediates such as geranyl pyrophosphate (GPP) and then farnesyl pyrophosphate (FPP). The original 14C label has already been lost in the previous step, so FPP does not carry any 14C isotope from the acetyl-CoA.

Conversion to Lanosterol

Farnesyl pyrophosphate undergoes a series of cyclizations to form lanosterol. As the label was lost before the FPP stage, lanosterol does not contain any 14C from the original acetyl-CoA.

Identify Labeled Positions in Lanosterol

Since the 14C label is lost during the conversion from mevalonate to IPP, there are no labeled positions in the lanosterol molecule when following the mevalonate pathway from labeled acetyl-CoA.

Key concepts

Acetyl-CoA

Acetyl-CoA is a key molecule in metabolism, at the heart of many biochemical reactions. Comprised of an acetyl group linked to coenzyme A, it plays a vital role in the mevalonate pathway.
The structure of acetyl-CoA features two carbon atoms in the acetyl group. These carbons are distinguished as the methyl carbon and the carboxyl carbon. In our exercise, the carboxyl carbon is noteworthy because it's labeled with a radioactive isotope, \(^{14}\text{C} \), which helps us trace its path in biochemical reactions.
Acetyl-CoA is not only the starting material in the mevalonate pathway but also a central player in energy production and lipid biosynthesis. By providing acetyl groups, which can be used in a wide array of cellular pathways, acetyl-CoA is essential for life.

Isoprenoids

Isoprenoids, or terpenoids, are a large and diverse class of organic compounds derived from five-carbon units known as isopentenyl pyrophosphate (IPP).
In the mevalonate pathway, IPP is synthesized from mevalonate—a transformation involving several key steps such as phosphorylation and decarboxylation.
The importance of isoprenoids lies in their role in numerous biological functions and their presence in various biomolecules:

• Hormones such as steroids
• Vitamins like Vitamin A, E, and K
• Precursors to essential molecules for growth and development

In the context of our exercise, although the carboxyl carbon of acetyl-CoA is initially labeled with \(^{14}\text{C} \), this label is lost during the decarboxylation process that converts mevalonate to IPP. Hence, the \(^{14}\text{C} \) label does not appear in the resulting isoprenoid products.

Lanosterol Biosynthesis

Lanosterol is a precursor to many steroids and an essential product of the mevalonate pathway. This pathway starts with simple molecules like acetyl-CoA and progresses through a network of reactions to produce complex sterols.
Once mevalonate is converted through several intermediary steps into farnesyl pyrophosphate (FPP), cyclization processes occur to transform FPP into lanosterol.
This cyclization is intricate, involving the formation of multiple steroid rings characteristic of lanosterol.However, due to the loss of the \(^{14}\text{C} \) label in earlier steps, specifically during the decarboxylation that produces IPP, there are no \(^{14}\text{C} \) labels in lanosterol when starting from labeled acetyl-CoA.
While the labeling doesn't help in finding positions in lanosterol, it underscores the pathway's complexity and the meticulous nature of sterol biosynthesis.