A BEGINNER’S GUIDE TO UREA SYNTHESIS | DON STEVE BLOG
March 28, 2024

Introduction

Urea is a compound that is produced in the liver from excess amino acids and other nitrogenous wastes. The synthesis of urea from ammonia and carbon dioxide is called the urea cycle or the Krebs-Henseleit cycle.

The urea cycle consists of several enzymatic reactions that take place in the liver. The first step involves the combination of ammonia and carbon dioxide to form carbamoyl phosphate, which is catalyzed by the enzyme carbamoyl phosphate synthetase I (CPS I). This enzyme requires ATP as an energy source.

The next step involves the transfer of the carbamoyl group from carbamoyl phosphate to ornithine to form citrulline. This reaction is catalyzed by the enzyme ornithine transcarbamylase (OTC).

Citrulline is then transported from the mitochondria to the cytosol, where it reacts with aspartate to form argininosuccinate. This reaction is catalyzed by the enzyme argininosuccinate synthetase.

Argininosuccinate is then cleaved to form arginine and fumarate by the enzyme argininosuccinate lyase. Arginine is then hydrolyzed to form urea and ornithine by the enzyme arginase.

Ornithine is then transported back to the mitochondria to participate in another round of the urea cycle.

Overall, the urea cycle converts toxic ammonia into urea, which is excreted from the body through the kidneys. The urea cycle is essential for the normal functioning of the body and any defects in the cycle can lead to serious health problems.

 

Formation of urea from ammonia

Urea is formed in the liver from ammonia, which is produced during the breakdown of amino acids in the body. The formation of urea from ammonia involves several steps, including:

  1. Deamination: Amino acids are deaminated in the liver, which removes their amino groups (-NH2) to form ammonia (NH3) and a keto acid.
  2. Ornithine cycle: The liver combines ammonia with carbon dioxide (CO2) to form carbamoyl phosphate, which reacts with ornithine to form citrulline. Citrulline is transported to the kidneys, where it is converted back to arginine, which is then used to synthesize urea.
  3. Urea synthesis: In the liver, arginine is hydrolyzed to form ornithine and urea. The urea is then transported to the kidneys and excreted in the urine.

Overall, the process of converting ammonia to urea is known as the urea cycle, and it is an important mechanism for removing toxic ammonia from the body.

 

Liver Lobule Functions

The liver is an important organ responsible for a variety of functions, including detoxification, metabolism, and the production of bile. The liver lobule is the basic functional unit of the liver, and it is composed of different zones, including the periportal zone, which is located around the portal triad, and the pericentral zone, which is located around the central vein.

Periportal cells of the liver lobule are characterized by their location around the portal triad and their unique functions, which include the uptake and processing of nutrients, such as glucose, amino acids, and lipids, as well as the detoxification of various substances, such as drugs and alcohol. These cells are also responsible for the production of bile, which is then transported to the bile ducts and eventually to the small intestine.

In terms of intra-cellular compartmentation, periportal cells contain various organelles, including the endoplasmic reticulum, Golgi apparatus, mitochondria, and lysosomes, which are involved in different metabolic pathways and functions. For example, the endoplasmic reticulum is responsible for the synthesis and processing of proteins, lipids, and carbohydrates, while the mitochondria are involved in energy production through oxidative phosphorylation. The Golgi apparatus is responsible for the modification, sorting, and packaging of proteins and lipids, while lysosomes are involved in the breakdown of cellular waste and debris.

Overall, the periportal cells of the liver lobule are highly specialized and compartmentalized, with different organelles and metabolic pathways contributing to their unique functions in nutrient uptake, detoxification, and bile production.

 

Urea cycle regulation

The urea cycle is a biochemical pathway that plays a critical role in the removal of ammonia, a toxic byproduct of protein metabolism, from the body. The control of the urea cycle involves both acute and chronic regulation.

Acute regulation of the urea cycle involves the control of enzyme activity, with the first step of the pathway, catalyzed by carbamyl-phosphate synthetase (CPS), being the most important. CPS is regulated allosterically by N-acetylglutamate (NAG), which is synthesized from glutamate and acetyl-CoA. When protein intake is high, the concentration of NAG increases, activating CPS and promoting the flow of metabolites through the urea cycle.

Chronic regulation of the urea cycle involves the induction of urea-cycle enzymes with a high-protein diet. The transcription of the genes encoding these enzymes is upregulated by transcription factors such as CREB and C/EBP, which are activated by the increased levels of amino acids in the diet. This leads to an increase in the expression of urea-cycle enzymes, increasing the capacity of the pathway to remove ammonia from the body.

Overall, the control of the urea cycle is complex and involves both acute and chronic regulation to ensure the proper removal of ammonia from the body.

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