What are the key aspects and clinical significance of the pentose phosphate pathway, fatty acid biosynthesis and degradation, amino acid metabolism, nucleotide metabolism, and metabolic integration during fed and fasting conditions?

From the Guidelines

The pentose phosphate pathway (PPP) is a crucial metabolic pathway that generates NADPH for reductive biosynthesis and produces ribose-5-phosphate for nucleotide synthesis, with significant implications for morbidity, mortality, and quality of life in various clinical scenarios, as highlighted in recent studies 1. The PPP consists of two phases: the oxidative phase and the non-oxidative phase. In the oxidative phase, glucose-6-phosphate is converted to ribulose-5-phosphate while generating NADPH. This phase involves three enzymes, with glucose-6-phosphate dehydrogenase (G6PD) being the rate-limiting enzyme. The non-oxidative phase involves the interconversion of various sugar phosphates through transketolase (which requires thiamine pyrophosphate as a cofactor) and transaldolase reactions, connecting the PPP to glycolysis. NADPH produced in the PPP is crucial for reductive biosynthesis, including fatty acid synthesis, cholesterol synthesis, and detoxification reactions, as well as protecting cells against oxidative stress by maintaining glutathione in its reduced form, which is essential for preventing oxidative damage and promoting overall health 1. G6PD deficiency is the most common enzyme deficiency worldwide and can lead to hemolytic anemia when exposed to oxidative stress from certain drugs, infections, or fava beans, emphasizing the importance of early diagnosis and management to prevent long-term complications and improve quality of life 1. The nitro blue tetrazolium (NBT) test is used to diagnose NADPH oxidase deficiency, which causes chronic granulomatous disease characterized by recurrent bacterial and fungal infections due to impaired neutrophil function, highlighting the need for prompt diagnosis and treatment to reduce morbidity and mortality. Understanding the PPP is essential for comprehending various metabolic disorders and their clinical manifestations, and recent studies have shed light on the significance of the PPP in different clinical scenarios, including the use of ketogenic diets for weight loss and metabolic control 1. Key aspects of the PPP include:

• The generation of NADPH for reductive biosynthesis and antioxidant defenses
• The production of ribose-5-phosphate for nucleotide synthesis
• The connection to glycolysis through the non-oxidative phase
• The clinical implications of G6PD deficiency and NADPH oxidase deficiency
• The role of the PPP in metabolic disorders, such as diabetes and obesity, and the potential benefits of ketogenic diets in improving metabolic control and reducing morbidity and mortality 1.

From the Research

Pentose Phosphate Pathway

• The pentose phosphate pathway (PPP) is a metabolic pathway that branches from glucose 6-phosphate (G6P) and produces NADPH and ribose 5-phosphate (R5P) 2, 3, 4.
• The PPP is divided into two phases: the oxidative phase and the non-oxidative phase 3.
• The oxidative phase converts glucose 6-phosphate into carbon dioxide, ribulose 5-phosphate, and NADPH, and is highly active in most eukaryotes 3.
• The non-oxidative phase metabolizes glycolytic intermediates and sedoheptulose sugars, yielding ribose 5-phosphate for nucleic acid synthesis and sugar phosphate precursors for amino acid synthesis 3.

Significance of NADPH

• NADPH is involved in redox homoeostasis and promotes biosynthetic processes, such as nucleotide synthesis, fatty acid synthesis, and cholesterol synthesis 4.
• NADPH plays a critical role in suppressing oxidative stress, including in certain cancers, where PPP inhibition may be therapeutically useful 4.
• NADPH also supports the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) for signaling and pathogen killing 4.

Correlation with Glycolysis

• The non-oxidative phase of the PPP can supply glycolysis with intermediates derived from ribose 5-phosphate and vice versa, depending on the biochemical demand 3.
• The PPP and glycolysis are interconnected, and the regulation of one pathway can affect the other 3.

Deficiencies and Clinical Implications

• Genetic deficiencies in the PPP, such as glucose-6-phosphate dehydrogenase (G6PD) deficiency, can result in haemolytic anaemia and infections due to lack of leucocyte oxidative burst 4.
• G6PD deficiency typically manifests as haemolytic anaemia due to red cell oxidative damage, but in severe cases, it can also result in infections due to lack of leucocyte oxidative burst 4.