BIOCHEM 3.8 - NEUROCHEMISTRY

• Lecture 7 is about Neurochemistry for Block 3.

General Concept for Enzyme Deficiencies

• Enzyme deficiencies can disrupt metabolic pathways.
• A substrate (S) is converted into products (P) through a series of reactions.
• A mutant enzyme can block the conversion of a substrate into its product.
• This can lead to an accumulation of the substrate and a deficiency in the products.
• The substrate S is normally metabolized into S1, S2, and S3, and is converted into a product P.
• Product P is further processed into P1 and P2.

Objectives

• Compare and contrast the neurotransmitters Acetylcholine, Dopamine, Norepinephrine, Epinephrine, Serotonin, GABA, and substance P.
• Summarize neurotransmitter synthesis and degradation, focusing on substrates, enzymes, metabolic products, and specific cell types.
• Explain BH4 metabolism and identify consequences of its disruption.
• Link substrates with pathways like the pentose phosphate pathway (NADPH) and amino acids (glutamate, tyrosine, and tryptophan).
• Explain limitations of inborn errors of metabolism in neurotransmitter synthesis and consequences of pathogenic variation.

Case 14

• A 3-year-old girl has a condition related to neurotransmitter deficiencies.
• She was born to a consanguineous marriage and has a family history of death and neurological illness.
• She displays psychomotor delay, hypotonia, epileptic encephalopathy, abnormal movements, and dysautonomia.
• She exhibits hyperphenylalanemia.

Neuron Composition: Cell Body (Soma)

• Neurons have a cell body (soma), a single nucleus, and a prominent nucleolus.
• They contain chromatophilic (Nissl) substance, which are large masses of organelles for protein synthesis.
• They also have abundant neurofilaments for organelle movement and are mostly located in the central nervous system (CNS).

Neuron Composition: Dendrites

• Dendrites are numerous elongated processes.
• They are specialized to receive stimuli from other neurons at synapses.

Neuron Composition: Axon

• Axons are a single long process originating at the axon hillock that sends information.
• Axons comprise nerves.
• They contain axoplasma, mitochondria, neurofilaments, microtubules, and transport vesicles surrounded by axolemma (plasma membrane).
• Axons can also receive impulses.

Neurotransmitters

• Neurotransmitters are chemicals involved in cell-to-cell synaptic transmission in the CNS or PNS.
• Each neuron produces a characteristic transmitter.
• Classes of neurotransmitters include:
  • Acetylcholine (Ach)
  • Monoamines (dopamine, norepinephrine, epinephrine, and serotonin)
  • Neuropeptides (substance P)
  • Simple amino acids (GABA, glutamic acid, aspartic acid, and glycine)
• Glucose is an important carbon source for the synthesis of both amino acids and neurotransmitters.
• Glutamate is a major excitatory neurotransmitter and GABA precursor.

Cofactors and Their Role in Neurotransmission

• Enzyme function depends on cofactors.
• Enzyme function is impaired or lost in the absence of cofactors.
• Tetrahydrobiopterin (BH4) is essential for phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase.
• Loss of BH4 results in hyperphenylalaninemia.
• BH4 metabolism correlates with the development of disorders.
• Cofactors are produced by complex, regulated pathways, marking significant areas of pathway cross-talk.
• BH4 is oxidized in hydroxylation reactions and must be regenerated.
• Dihydropteridine reductase (DHPR) and pterin-4a-carbinolamine dehydratase (PCD) regenerate BH4.

Acetylcholine

• Acetylcholine is the only neurotransmitter used at the neuromuscular junction.
• It's released from all preganglionic and most postganglionic neurons in the PNS.
• It's released from all preganglionic neurons in the sympathetic nervous system and presynaptic neurons of the adrenal medulla.
• Choline and Acetyl CoA are combined to synthesize Acetylcholine, which is then broken down into Choline and Acetate.

Phenylalanine Metabolism

• Dietary phenylalanine is processed into tyrosine via phenylalanine hydroxylase.

Dopamine, Norepinephrine, and Epinephrine

• The presence of pathway components determines the neurotransmitter secreted.
• Dopaminergic neurons only have tyrosine hydroxylase and dopa decarboxylase and primarily secrete dopamine.
• Adrenergic neurons also have dopamine beta-hydroxylase and secrete norepinephrine.
• The adrenal medulla has the complete pathway and secretes primarily epinephrine.

Serotonin

• Serotonergic neurons produce serotonin from tryptophan, mainly in the brain and gastrointestinal tract.
• Serotonin also serves as a precursor to melatonin.

GABA

• GABA is an inhibitory neurotransmitter and amino acid found in GABAergic neurons.
• GABA does not have other metabolic functions and isn't incorporated into proteins.
• Glutamate is converted into GABA.

Transitory Fetal Transmitters and Development

• Fetal cerebellum at the midgestation contains substance P and somatostatin.
• The mature cerebellum does not contain substance P.
• Substance P, an 11 amino acid neuropeptide, is part of the tachykinin neuropeptide family.
• It plays a role in pain perception (altering signaling), cell proliferation, chemotherapy side effects, and neuroinflammatory damage.

Disorders of Neurotransmitter Synthesis

• Developmental disorders of neurotransmitter synthesis from inborn errors are often incompatible with survival, especially for acetylcholine, monoamines, or essential peptides.
• Amino acid-associated metabolic defects are associated with intellectual disability, epilepsy, and neurological disorders, like phenylketonuria (PKU).

Dihydropteridine Reductase Deficiency (DHPR-D)

• DHPR-D is a rare autosomal recessive condition caused by pathogenic variation in the quinoid dihydropteridine reductase (QDPR) gene.
• BH4 biosynthesis is intact, but the condition has a worse prognosis than primary BH4 deficiencies.
• This outcome is particularly true if the primary BH4 deficiency does not present with hyperphenylalanemia.
• Accumulation of 7,8-dihydrobiopterin (BH2) blocks catecholamine and serotonin synthesis.