Succinate-Coenzyme A Ligase Deficiency - Causes, Symptoms, and Management

Introduction:

Succinate-coenzyme A ligase deficiency is an inherited disorder that affects the early development of the brain and other body systems. It is an enzyme in the Krebs cycle (citric acid cycle or tricarboxylic acid cycle) that converts succinate-CoA to succinate and free Co-enzyme A. It converts ADP (adenosine diphosphate) or GDP (guanosine diphosphate) to ATP (adenosine triphosphate) or GTP (guanosine triphosphate). ATP is the source of energy for the body and it is stored in the cells. The ATP is made up of ribose sugar, adenine base (nitrogenous base), and three bonded phosphate groups. ATP is continuously synthesized from ADP. ADP is produced in the body continuously through cellular respiration. Cellular respiration is a catabolic process in which nutrients are broken down into energy. This process requires oxygen which the cells get through respiration.

What Is Krebs Cycle?

Krebs cycle is a catabolic process that occurs in every cell of the human body for the generation of energy. In Kreb’s cycle, the product at the end is used to restart the cycle for energy production. ATP (adenine triphosphate) is produced at the end of Kreb’cycle as an energy source for the body. Succinate CoA is converted into succinic acid in the presence of succinate CoA ligase. 1 GTP and 1 ATP are produced during the conversion.

• Glucose metabolism occurs through a process called glycolysis. It produces ATP and three-carbon compound pyruvate.

• The pyruvate is transported to the mitochondria, where it is converted to acetyl CoA. The acetyl-CoA enters Krebs’ cycle to produce ATP. The acetyl-CoA is oxidized to form CO2 (carbon dioxide) and ATP. The energy obtained from the Krebs cycle is crucial for the development of the endothelial system and the formation of lymphatic and blood vessels.

• Kreb’s cycle is also called a citric acid cycle or TCA cycle. This cycle is a special metabolic pathway that runs in mitochondria. Most cells have mitochondria.

• Red blood cells do not have mitochondria. So they cannot run the Krebs cycle. The proteins, carbohydrates, and lipids we take are metabolized into acetyl CoA. Acetyl CoA serves as a fuel for the cells.

• Succinate CoA ligase is a significant intermediate in the Krebs cycle. It is produced from alpha-ketoglutarate by the action of the enzyme alpha-ketoglutarate dehydrogenase.

• The fifth step of the Kreb cycle is the conversion of succinyl CoA into succinate. The succinyl CoA is acted upon by the enzyme succinate Co- A synthetase to produce succinic acid.

• Succinate CoA is converted into succinate by succinate CoA ligase enzyme in which CoA is released out, and during this process, GDP is converted into GTP.

• During the course of the action, one molecule of GTP is generated due to substrate-level phosphorylation. The GTP transfers its phosphate group to ADP to form an ATP molecule.

• Any alteration of the cycle can increase cortisol. The increased cortisol alters the metabolism of the placenta and fetal development, including heart function, which can be fatal. Kreb’s cycle plays a role in the interconversion of amino acids. It also plays a role in lipogenesis (fatty acid and triglyceride synthesis).

What Is the Role of Succinate-Coenzyme A Ligase?

Succinyl CoA has an important role in mitochondria in which the enzyme plays a series of chemical reactions called the citric acid cycle or Kreb’s cycle. The reactions use oxygen and generate energy. The succinyl CoA enzyme interacts with another enzyme called nucleoside diphosphate kinase that produces the building blocks of the DNA in mitochondria.

What Are the Causes of Deficiency of Succinate-Coenzyme A Ligase?

The causes of succinate- CoA Ligase deficiency is due to:

• Succinyl coenzyme deficiency is an autosomal recessive disorder. Both the copies of the genes SUCLA1 and SUCLA 2 have mutations. These genes encode for subunits of adenosine diphosphate-dependent isoforms of succinyl-coenzyme A synthase. The mutations in these genes lead to impaired oxidative phosphorylation and reduced adenosine triphosphate (ATP) generation.

• Succinyl-CoS ligase deficiency is due to a mutation in the genes SUCLA2 gene or SUCLG1 gene. These genes provide instructions for making the enzyme succinate-CoA ligase. The mitochondria in the cell convert the food energy into energy that can be used by the cells.

• The succinyl CoA ligase enzyme plays a crucial role in the mitochondria. Mitochondrial DNA is essential for the functioning of the structures. The enzyme forms the building blocks of mitochondrial DNA.

• The gene mutations can disruption in the function of the enzyme. If there is a deficiency in enzyme production it directly affects the production of mitochondrial DNA. It impairs the mitochondrial function in many cells.

• It is also called mitochondrial DNA depletion syndrome or mitochondrial DNA depletion encephalomyopathic form with methylmalonic aciduria.

What Are the Symptoms Caused by Succinate-Coenzyme A Ligase Deficiency?

The symptoms of the disease include:

It is an inherited disorder that affects the brain and other body systems.

• A few individuals have a more severe form of deficiency that causes fatal infantile lactic acidosis.

• Infants develop lactic acid in the body which is very toxic that leads to difficulty in breathing and muscle weakness. Such babies can survive only for a few days after birth. Many children have reduced muscle mass and muscle weaknesses that make standing and walking more difficult.

• There can be progressive abnormal curvature of the spine (scoliosis), severe hearing loss, and seizures. Most children can gain weight and grow slower than expected.

• The deficiency causes hypotonia that delays motor skill development like holding up the head and uncontrolled movements (dystonia). The symptoms of hypotonia occur in the first few months after birth in the baby.

• A substance methylmalonic acid builds up in the body and is excreted in the urine known as methylmalonic aciduria.

• Recurrent infections in the respiratory tract and breathing difficulties.

• The children can live up to adolescence and after that, they fail to survive.

Conclusion:

The interaction of succinyl CoA ligase with nucleotide diphosphate kinase is involved in mitochondrial nucleotide metabolism. It is a mitochondrial matrix enzyme. Mutations in the gene SUCLA2 can cause a deficiency of the enzyme that causes deafness, hypotonia, and infantile lactic acid acidosis.