Serine Metabolism and Biosynthesis Disorders

Serine is a non-essential amino acid that functions as a precursor for proteins, nucleotides and lipids, as well as for the synthesis of the neurotransmitter D-serine. In human cells serine is produced predominantly via the phosphorylated pathway, a three-step diversion of glycolysis mediated by 3-phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT) and phosphoserine phosphatase (PSP). This pathway is believed to form a dynamic metabolon, often termed the ‘serinosome’, to enhance flux and coordinate enzyme activity. Genetic defects in any of these enzymes give rise to serine deficiency disorders, a group of inborn errors of neurometabolism characterised by microcephaly, seizures and psychomotor impairment. Phenotypic severity ranges from fatal prenatal presentations to milder forms manifesting as developmental delay or peripheral neuropathy. Early intervention with L-serine supplementation has become a mainstay of therapy, often alleviating seizures and improving developmental outcomes. Beyond inherited deficiencies, dysregulated serine biosynthesis has been implicated in oncogenesis, as tumour cells upregulate components of the pathway to support rapid proliferation. Understanding the molecular basis of enzyme dysfunction and its clinical consequences remains a critical focus of research with wide-ranging therapeutic implications.

Research from Nature Portfolio

Recent work has illuminated the impact of a recurrent missense variant in the gene encoding phosphoserine phosphatase. The Asn133Ser substitution impairs the stability of PSP without altering its catalytic efficiency in isolation. Cellular studies reveal that this variant disrupts the integrity of the serinosome, reducing the abundance of pathway enzymes and leading to perinuclear aggregation. Patient fibroblasts carrying the homozygous change exhibit marked decreases in L-serine, D-serine and glycine levels. These findings provide a mechanistic link between enzyme instability and neurometabolic dysfunction, and suggest strategies to stabilise the serinosome as a potential therapeutic approach.

Serine Metabolism and Biosynthesis Disorders publication trend

The graph below shows the total number of articles in serine metabolism and biosynthesis disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Phosphorylated pathway: The three-step metabolic route converting 3-phosphoglycerate from glycolysis into L-serine via PHGDH, PSAT and PSP.

Serinosome: A proposed multiprotein complex that organises the enzymes of serine biosynthesis to enhance metabolic flux.

Serine deficiency disorders: A group of genetic neurometabolic diseases caused by mutations in enzymes of the serine biosynthesis pathway, leading to reduced serine levels and neurological impairment.

Phosphoserine aminotransferase (PSAT): The PLP-dependent enzyme that catalyses the second step of serine biosynthesis, transferring an amino group to form phosphoserine.

Phosphoserine phosphatase (PSP): The enzyme that catalyses the irreversible dephosphorylation of phosphoserine to form L-serine, driving pathway flux.

References

1. L‐serine biosynthesis in the human central nervous system: Structure and function of phosphoserine aminotransferase. Protein Science (2023).
2. Constructing and interpreting a large-scale variant effect map for an ultrarare disease gene: Comprehensive prediction of the functional impact of PSAT1 genotypes. PLOS Genetics (2023).
3. L-serine deficiency: on the properties of the Asn133Ser variant of human phosphoserine phosphatase. Scientific Reports (2024).