Biochemistry Ch 48 903-926
Metabolism of Nervous System
Cell Types of Nervous System – consists of neurons and neuroglia (oligodendrocytes and
astrocytes = glial cells, microglial cells, ependymal cells, Shwann cells)
-neuroglia support and sustain neurons by surrounding them and holding them in place,
supplying nutrients and O2, and insulating them for quicker conduction
Neurons – have soma containing long axon and short dendrites; dendrites receive information
from axons and axons transmit information to other neurons
-axon-dendrite connection is known as synapse
-most neurons have multiple dendrites, and most axons branch to multiple targets (divergence)
-signaling requires neurotransmitter binding to receptor to initiate electrical signal
-injured neurons have limited capacity for regeneration
Astrocytes – found in CNS, star-shaped, and provide physical/nutritional support for neurons
-astrocytes guide neuronal migration to final adult position during development and secrete
matrix in order to hold neurons in place
-astrocytes phagocytize debris left by cells, provide lactate (from glucose metabolism) as a
carbon source for neurons, and control brain extracellular ionic environment
Oligodendrocytes – myelinate CNS neurons; myelin is lipid-protein covering of axons
-oligodendrocytes form myelin sheaths around multiple neurons in CNS by sending out
processes that bind to axons on target neurons
-speed of neuron conduction is directly proportional to degree of myelination
-oligodendrocytes support similar to astrocytes, and have limited regeneration capability
Schwann Cells – supporting cells of PNS and act to form myelin sheaths around axon; unlike
oligodendrocytes, Schwann cells can only myelinate ONE axon
-Schwann cells clean up cellular debris in PNS and help peripheral axon regeneration
Microglial Cells – smallest glial cells; they are immunologically responsive similar to
macrophages and they destroy microorganisms/phagocytize debris
Ependymal Cells – ciliated cells lining cavities (ventricles) of CNS and spinal cord; these cells
secrete cerebrospinal fluid (CSF) into ventricular system, and beating of ependymal cilia allows
for efficient circulation of CSF
-CSF acts as shock absorber and a system of removing metabolic wastes
-cells in ependymal layer can act as neural stem cells, which can regenerate into neurons
Blood Brain Barrier (BBB)
Capillary Structure – in most organs, rapid passage of molecules occurs from blood through
endothelial wall of capillaries into interstitial fluid, and interstitial fluid resembles blood
-in brain, transcapillary movement of substrates from circulation is restricted due to BBB, which
limits accessibility of toxins and harmful compounds to neurons in CNS
-BBB begins with endothelial cells forming inner lining of vessels supplying blood to CNS; these
endothelial cells are joined by tight junctions that don’t permit movement of POLAR
MOLECULES from blood into interstitial fluid that bathes neurons.
-Also, the endothelial cells in CNS lack mechanisms for transendothelial transport such as
fenestrations (pores) or transpinocytosis (vesicular transport from one side to the other)
-endothelial cells contain drug-metabolizing enzymes found in liver, so that they can metabolize
toxic chemicals and neurotransmitters as an enzyme-forming barrier
-they actively pump hydrophobic molecules that diffuse into endothelial cells back into
blood with P-glycoproteins, which act as transmembranous, ATP-dependent pumps
-further BBB protection comes from continuous collagen-containing basement membrane that
surrounds capillaries surrounded by foot of astrocytes
-compounds must pass through endothelial cell membranes, enzymatic barrier, basement
membranes, and astrocyte cell barriers to get to CNS neurons
Transport Through Blood Brain Barrier – nonpolar compounds: drugs/gases can diffuse
through. Non-essential fatty acids CANNOT cross, essential fatty acids CAN cross
1. Fuels – glucose is principal fuel of brain, and is transported thorugh endothelial
membranes by facilitated diffusion by the GLUT-1 transporter
a. GLUT-3 on neurons then allow neurons to transport glucose from ECF
b. GLUT-1 is also found on glial cells
c. Rate of glucose transport into ECF normally exceeds rate of energy metabolism,
but in hypoglycemic states, glucose is reduced to lower than Km for GLUT-1 in
endothelial cells of barrier
d. Monocarboxylic acids (lactate, acetate, pyruvate, acetoacetate, Bhydroxybutyrate) are transported by separate system slower than glucose
e. Facilitated glucose transporter protein type I (GLUT-1) deficiency syndrome –
glut-1 transporters are impaired resulting in low glucose concentration in CSF
(known as hypoglycorrhachia); diagnostic is normal blood glucose and low CSF
levels; clinical features are seizures, developmental delay, motor disorder
2. Amino Acids and Vitamins – Large Neutral Amino Acids (LNAAs) such as F, L, Y, I, V, W,
M, and H all enter CSF rapidly via single AA transporter; many are essential in diet and
must be imported for protein synthesis or as neurotransmitter precursors
a. All of these amino acids compete for transporter binding
b. Entry of small amino acids (A, G, P, and GABA) Is restricutred because they could
change content of neurotransmitters, and instead are synthesized in brain and
transported out of CNS via the Alanine-preferring system carrier
c. If one AA is in excess, it can compete for binding to the single transporter to
lower transport of the other amino acids, providing a reason for the mental
retardation seen in phenylketonuria caused by high phenylalanine
3. Receptor Mediated Transcytosis – proteins such as insulin, transferrin, and IGFs cross
BBB by receptor-mediated transcytosis; protein binds membrane receptor, then
complex is endocytosed into a vesicle and released on other side of endothelial cell
a. Absorptive-mediated endocytosis can occur where protein binds
nonspecifically to membrane and not a distinct receptor
Synthesis of Small Nitrogen-Containing Neurotransmitters – neurotransmitters fall into 2
categories: small nitrogen-containing molecules and neuropeptides
-small nitrogen containing molecules are: GABA, glycine, acetylcholine, dopamine,
norepinephrine, serotonin, histamine, epinephrine, aspartate, nitric oxide
-each neuron synthesizes only the neurotransmitter it uses for transmission
-neuropeptides are small peptides synthesized and processed in CNS; some have targets in CNS
(endorphins binding to opioid receptors to block pain), whereas others are released into
circulation and bind to receptors on other organs, such as GH and TSH
-many neuropeptides are synthesized as larger precursors later cut
-neurons can contain all kinds of varieties of small molecule/neuropeptide neurotransmitters
General Features of Neurotransmitter Synthesis – most are synthesized from amino acids,
intermediates of glycolosys and TCA, and O2 in cytoplasm of presynaptic cell
-rate of synthesis regulated to relate to rate of neuron firing
-synthesis occurs in cytoplasm of presynaptic nerve terminal; enzymes synthesized in soma and
transported to nerve terminal
-neurotransmitters transported into vesicles by ATP-pump linked with proton gradient
-release of storage vesicle triggered by impulse depolarizing membrane = influx of Ca to
promote vesicle fusion with synaptic membrane and release of neurotransmitter
-action of neurotransmitter is terminated through reuptake into presynaptic terminal, uptake
into glial cells, diffusion away from synapse, or enzymatic inactivation
-Drugs have been developed to block neurotransmitter uptake into storage vesicles; Reserpine
blocks catecholamine uptake into vesicles, had been used as antihypertensive/antiepileptic
Dopamine, Norepinephrine, Epinephrine:
1. Synthesis of the Catecholamine Neurotransmitters – dopamine, norepinephrine, and
epinephrine are synthesized from a common pathway starting at TYROSINE, which is
supplied by diet or converted to from phenylalanine by phenylalanine hydroxylase
a. RATE LIMITING STEP in synthesis of neurotransmitters from tyrosine is
hydroxylation of tyrosine by tyrosine hydroxylase (requires hydrobiopterin BH4)+),
and the product formed is dihydroxyphenylalanine DOPA
b. Second step is decarboxylation of DOPA  dopamine, requiring pyridoxal
phosphate (vitamin B6); dopaminergic neurons STOP synthesis here
c. Neurons synthesize epinephrine from dopamine in a hydroxylation reaction
catalyzed by dopamine β-hydroxylase (DBG), present only in storage vesicles
i. Enzyme requires electron donor from vitamin C; Cu2+ also required
d. Epinephrine synthesized by adrenal medulla AND few neurons; the neurons
synthesize epinephrine from norepinephrine with the enzyme phenylethanolamine
N-Methyl transferase that uses S-adenosylmethionine (SAM) as a methyl donor to
norepinephrine  epinephrine
2. Storage and Release of Catecholamines – low concentrations of catecholamines are free in
cytosol and high concentrations are inside vesicles; conversion of L-dopa  dopamine
occurs in cytosol after which dopamine is stored in vesicles.
a. norepinephrine-containing neurons: final β-hydroxylation reaction is inside vesicle
b. catecholamines are transported into vesicles by VMAT2, a protein homologous to
bacterial drug-resistant transporters (P-glycoprotein)
c. mechanism of transport in storage vesicles is an ATP-dependent process linked to
proton pump; protons pumped into vesicles by vesicular ATPase (V-ATPase);
protons then exchange for catecholamine by VMAT2
d. in vesicles, catecholamines exist in complex with ATP and acidic proteins known as
chromogranins
i. elevated chromogranins can be found in patients with neuroendocrine
tumors such as pheochromocytomas
e. vesicles maintain supply of catecholamines at nerve terminal available for
immediate release, AND they mediate process of release; when action potential
reaches nerve, Ca channels open to allow influx of Ca to promote fusion of vesicles
with neuronal membrane; vesicles discharge contents, including neurotransmitters,
ATP, chromogranins, and DBH by exocytosis
3. Inactivation and Degradation of Catecholamine Neurotransmitters – action is terminated
through REUPTAKE into presynaptic terminal and diffusion away from synapse. Also,
degradative enzymes are present in presynaptic terminal and glial + endothelial cells
-Two major reactions in process of inactivation/degradation are catalyzed by monoamine
oxidase (MAO) and catechol-O-methyltransferase (COMT)
-MAO – on outer mitochondrial membrane of many cells and oxidizes carbon containing
amino group to an aldehyde to release NH4
-in presynaptic terminal, MAO inactivates catecholamines not protected in vesicles
-MAO-A preferentially deaminates norepinephrine and serotonin
-MAO-B acts on wide spectrum of phenylethylamines
-MAO in liver protects against ingestion of dietary amines such as tyramine from cheese
-tyarmine is degradation product of tyrosine, can cause headaches, palpitations,
nausea, vomiting, and elevated blood pressure; leads to norepinephrine release
-tyramine is inactivated by MAO-A
COMT – found on many cells including RBC and works on a broad spectrum of extraneuronal
catechols diffused away from synapse
-COMT transfers methyl from SAM to OH group on cateholamine or its degradation
product. Because it uses SAM, it is dependent on vitamin B12 and folate
-cerebrospinal homovanillylmandelic acid (HVA) is indicator of dopamine degradation
-in albinism, either Cu-dependent tyrosine hydroxylase of melanocytes or other enzymes
converting tyrosine to melanins is defective
4. Regulation of Tyrosine Hydroxylase – since this enzyme is the rate-limiting step in
catecholamine synthesis, it is heavily regulated by FEEDBACK INHIBITION coordinated with
depolarization of nerve terminal
-also inhibited by free cytosolic catecholamines
-depolarization of nerve terminal activates enzyme and activates several protein kinases to
phosphorylate tyrosine hydroxylase to cause it to bind more tightly to BH4, making it less
sensitive to product inhibition
-long-term process involves alterations in amounts of tyrosine hydroxylase and dopamine Bhydroxylase present in nerve terminals
-when sympathetic activity is increased, mRNA for tyrosine hydroxylase and dopamine
B-hydroxylase are increased in soma, resulting from phosphorylation of CREB by kinases
-CREB binds CRE in promoter of gene to stimulate enzyme
Metabolism of Serotonin – serotonin is synthesized from TRYPTOPHAN in a similar method to
the pathway of norepinephrine from tyrosine
-first step uses tryptophan hydroxylase and requires BH4 to hydroxylate the ring of tryptophan
-seconds step is decarboxylation catalyzed by same enzyme that decarboxylates DOPA
-Serotonin can be inactivated by the enzyme MAO
-melatonin is also synthesized from tryptophan; produced in pineal gland in response to lightdark cycle (levels rise in blood in the dark), involved in circadian rhythms
-antipsychotic drugs were based on inhibiting MAO: Deprenyl (MAO-B specific), Clorgyline
(MAO-A specific), Moclobemide (MAO-A specific, reversible)
Metabolism of Histamine – histamine is produced by both mast cells and certain neuronal
fibers. Mast cells produced in the bone marrow and are present in thalamus, hypothalamus,
dura mater, leptomeninges, and choroid plexus
-histaminergic neuron bodies are found in tuberomammillary nucleus of posterior basal
hypothalamus and project fibers into all areas of CNS
-Histamine is synthesized from histidine in a single enzymatic step using histidine decarboxylase
requiring pyridoxal phosphate (vitamin B6), similar to dopa decarboxylase
-histamine is stored in nerve terminal vesicles; depolarization activates release of histamine
through Ca dependent mechanism
-histamine activates both postsynaptic AND presynaptic receptors, and it is NOT recycled into
presynaptic terminal
-astrocytes have high-affinity uptake system for histamine
-first step in histamine inactivation is methylation by histamine methyltransferase
which transfers methyl group from SAM to nitrogen group of histamine 
methylhistamine; second step is oxidation by MAO-B
-histamine is major mediator of allergic response  vasodilation and increased permeability of
vascular endothelium; bronchoconstrictor to remove allergic material… histamine in brain is an
excitatory neurotransmitter
Acetylcholine
1. Synthesis – acetylcholine is synthesized from acetyl CoA and choline, catalyzed by choline
acetyltransferase (ChAT) occurring in presynaptic terminal and ACh is stored in vesicles
released by Ca-mediated exocytosis
a. Choline is taken up by presynaptic terminal from blood via low-affinity (high Km)
system and from synaptic cleft via high-affinity (low Km) system; it is also derived
from hydrolysis of phosphatidylcholine in membrane lipids
b. Supply of choline in brain can become rate limiting for acetylcholine synthesis, and
so supplementing diet with lecithin increases brain acetylcholine in patients
suffering from tardive dyskinesia (involuntary movements of facial muscles/tongue)
c. Choline is component of diet but can also be synthesized for phospholipids by route
of triple methylation (taken from SAM) to ethanolamine portion of
phosphatidylethanolamine to form phosphatidylcholine; in brain and liver
i. Vitamin B12 is requirement for choline synthesis
d. Acetyl group used for acetylcholine synthesis is derived from glucose oxidation to
pyruvate and decarboxylation of pyruvate to form acetyl-Coa via pyruvate
dehydrogenase
2. Inactivation of Acetylcholine – inactivated by acetylcholinesterase, an enzyme that is
inhibited by wide variety of compounds and toxins
a. Neurotoxins such as Sarin
b. Acetylcholine is major neurotransmitter at neuromuscular junctions, inability to
inactivate it leads to constant activation of nerve-muscle synapses which can lead to
paralysis
Glutamate and γ-Aminobutyric Acid (GABA) –
1. Synthesis of Glutamate – glutamate is an excitatory neurotransmitter in CNS leading to
nerve depolarization and is synthesized de novo from GLUCOSE rather than picked up from
blood because it doesn’t cross BBB
a. Glutamate is synthesized from TCA cycle intermediate α-ketoglutarate and occurs
through 2 routes:
i. glutamate dehydrogenase reduces alpha-ketoglutarate to glutamate and
uses free ammonia (provided by AA degradation or diffusion across BBB)
ii. transamination reactions where amino group is transferred from other
amino acids to α-ketoglutarate to form glutamate
b. glutamate can be synthesized from glutamine using glutaminase
c. glutamate is stored in vesicles and its release is Ca dependent
d. glutamate is removed from synapse through high-affinity uptake systems in nerve
terminals and glial cells
2. GABA – major INHIBITORY neurotransmitter in CNS – it is synthesized by decarboxylation of
glutamate in a single step catalyzed by glutamic acid decarboxylase (GAD)
a. GABA is recycled in CNS by reactions called the GAGA Shunt which conserves
glutamate and GABA
b. Much of GABA uptake occurs in glial cells; GABA shunt in glial cells produces
glutamate, which is converted to glutamine and transported out of glial cells to
neurons, where it is converted back to glutamate
c. Glial cells lack GAD and cannot synthesize GABA
d. Tiagabine is a drug that inhibits reuptake of GABA from synapse to treat epilepsy
Aspartate – excitatory neurotransmitter synthesized by TCA cycle intermediate oxaloacetate
through transamination reactions; aspartate cannot cross BBB; functions in fewer pathways
compared to glutamate
Glycine – MAJOR INHIBITORY neurotransmitter in SPINAL CORD; synthesized de novo within
nerve terminal from SERINE by serine hydroxymethyltransferase requiring folic acid; serine is
synthesized from the intermediate 3-phosphoglycerate in glycolysis
-glycine is terminated via uptake by high-affinity transporter
Conversion of Arginine to Nitric Oxide – NO induces vasodilation, neurotransmission, and
activates immune system to kill tumors and parasites
-NO synthesized from arginine catalyzed by NO Synthase (NOS)
-NOS exists as tissue specific forms of two families of enzyme
-in macrophages, NOS overproduces NO to lead to cytotoxic effects on parasites and
tumors
-in nervous tissue, vascular endothelium, platelets, and other tissues, NO causes
vasodilation and neural transmission
-on target cells, NO activates guanylate cyclase  cGMP which in smooth muscle activates
protein kinases to relax and dilate smooth muscls
-smooth muscle relaxation permits corpus carvernosum to fill with blood to cause penile
erection by acting as neurotransmitter
-NO can cross membranes because it is a gas; NO may function retrograde to influence
neurotransmitter release from presynaptic terminal after diffusing from postsynaptic neuron
Metabolic Encephalopathies and Neuropathies – brain depends on blood for glucose and O2,
and it uses 20% of O2 supply of the body; during prolonged fasting, ketone bodies can be used
as fuel but they cannot totally substitute for glucose
-glucose  pyruvate in glycolysis, and pyruvate oxidized in TCA;
-anaerobic glycolysis yields 2ATP cannot sustain brain requirement of energy, which can only be
satisfied by complete oxidation of glucose to CO2, yielding 32 ATP per glucose
Hypoglycemic Encephalopathy – hypoglycemia encountered with malignancies producing
insulin, IGF, or chronic alcoholism; early signs include protective mechanisms initiated by
hypothalamic sensory nuclei such as sweating, palpitations, anxiety, and hunger  progress to
confusion, lethargy, seizures, coma
-as blood glucose falls below 2.5mM, brain tries to use substrates like glutamate and TCA
intermediates as fuels (but pool for these is small, and they are depleted)
-below 1mM glucose, ATP is depleted
-between 2.5mM and 2.0mM, symptoms appear to arise from decreased synthesis of
neurotransmitters in particular regions of brain rather than global energy deficit
-diminished aspartate, glutamate, GABA, and glycine from hypoglycemia
-below 1.0mM glucose, neuronal cell death occurs through involvement of glutamate
excitotoxicity
-occurs when cellular energy reserves are depleted; failure of energy-dependent
reuptake pumps results in buildup of glutamate in synaptic cleft and overstimulation of
postsynaptic glutamate receptors, leading to lethal influx of Ca to activate cytotoxic
intracellular pathways of postsynaptic neuron
Hypoxic Encephalopathy – cerebral energy metabolism is normal with mild-moderate hypoxia
that causes severe cognitive dysfunction (resulting from impaired neurotransmitter synthesis)
-in mild hypoxia, cerebral blood flow increases to maintain O2 to brain, anaerobic glycolysis is
accelerated to maintain ATP and increases lactate and fall of pH (results in coma)
-hypoxia can result from insufficient O2 reaching blood, severe anemia, or direct insult to O2
utilizing capacity of brain
-ALL forms result in diminished neurotransmitter synthesis
-Glutamate and GABA synthesis, which depend on functioning TCA cycle, are decreased
as a result of elevated NADH levels which inhibit TCA enzymes
-NADH levels increased when O2 is unavailable to accept eletrons from ETC and NADH
cannot be readily converted back to NAD
Relationship between Glutamate Synthesis and Anaplerotic Pathways of Pyruvate Carboxylase
and Methylmalonyl-CoA Mutase
-glutamate synthesis removes α-ketoglutarate from TCA cycle to decrease oxaloacetate
regeneration, making it necessary for oxaloacetate to be replaced by an anaplerotic reaction:
1. pyruvate carboxylase and
2. Degradative pathway of branched-chain AA valine and isoleucine which contribute succinylCoA to TCA cycle; uses vitamin B 12 in reaction catalyzed by methylmalonyl-CoA mutase
Lipid Synthesis in Brain and Peripheral Nervous System – portion of neuronal cell membrane
involved in neurotransmission has unique role in lipid synthesis and composition.
-at presynaptic terminal, lipid composition changes rapidly as storage vesicles containing
neurotransmitter fuse with cell membrane to release contents
-portions of membrane are lost as endocytic vesicles
-on postsynaptic terminal, membrane contains receptors for neurotransmitter and high
concentration of membrane signaling components such as phosphatidylinositol
-another feature of brain lipid metabolism is that BBB restricts entry of nonessential fatty acids
such as palmitate (released from adipose or present in diet)
-essential fatty acids are taken up by the brain
-brain is constantly synthesizing cholesterol, fatty acids, glycosphingolipids, and phospholipids
-neuronal signaling requires myelin, made from lipid-rich protein complexes
Brain Lipid Synthesis and Oxidation – virtually all lipids found at BBB must be synthesized within
CNS except for essential fatty acids (linoleic and linolenic acid)
-uptake of fatty acids into CNS is insufficient to meet metabolic demand, requiring aerobic
glycolytic metabolism
-very long chain fatty acids play a role in myelin sheath synthesis
-peroxisomal fatty acid oxidation is important in the brain because brain contains very long
chain fatty acids AND phytanic acid, both of which are oxidized in peroxisomes by alphaoxidation
-disorders affecting peroxisome biogenesis (refsum disease) severely affects brain cells
because of inability to metabolize branched-chain and very long chain fatty acids
Myelin Synthesis – myelin assists in rapid nerve conduction in PNS and CNS
-myelin is a multilayered lipid/protein structure formed from plasma membrane of glial cells
-Schwann cell in PNS myelinates ONE axon, oligodendrocyte myelinates multiple axons
in CNS
Myelin Lipids – as glial cell is converted to myelin, lipid composition changes; lipid:protein ratio
is increased, as is the contents of sphingolipids
-myelin is tightly packed and there are many hydrophobic interactions between lipids and
proteins for that to occur
-cerebrosides constitute 16% of total myelinlipid and are completely absent from other cell type
cell membranes
-predominant cerebroside – galactosylcerebroside has a single sugar attached to OH
group of sphingosine
-sphingomyelin is predominant lipid in myelin is present at same low concentration in
ALL cell membranes
-galactocerebrosides pack more tightly than phosphatidylcholine
-brain synthesized very long chain fatty acids which develop strong hydrophobic interactions
allowing close packing of myelin sheath
-high cholesterol content of membrane also contributes to tight packing
Myelin Structural Proteins – layers of myelin are held together by protein-lipid/protein-protein
interactions
-in CNS, two proteins constitute 60-80% of total proteins: proteolipid protein and myelin basic
protein (MBP)
-proteolipid protein is very hydrophobic that forms large aggregates in aqueous solution and is
resistant to proteolysis, thought to stabilize myelin structure
-MBPs are a family of proteins easily extracted from membrane and are soluble; major MBP has
no tertiary structure and is located on cytoplasmic face of myelin membranes
-antibodies against MBPs elicit experimental allergic encephalomyelitis, used for understanding
MS
-in PNS, major myelin protein is Po, glycoprotein accounting for 50% of PNS myelin, thought to
play a similar structural role in maintaining myelin structure as proteolipid protein in CNS
-MBP also found in PNS, designated P2
Demyelinating Diseases of CNS – best disease is MS, a progressive demyelination of CNS
without known cause; triggers formation of autoimmune antibodies against nervous system
components
-most well known presentation is relapsing-remitting type where early in the course of disease,
natural history is one of exacerbations followed by remission; eventually CNS cannot repair
damage accumulated over the years and remission occurs less frequently
-primary injury is loss of white matter, which interferes with neuronal conduction
-CNS compensates by stimulating oligodendrocyte to remyelinate damaged axon, and
when this occurs, remission is achieved
-remyelination often leads to slowing of conduction because it causes reduced myelin
thickness or shortening of intermodal distances
-eventually becomes difficult to repair myelin in large areas of CNS
-treatment of MS aims at blocking immune system
-other demyelinating diseases exist
-inherited mutations in Po (PNS myelin protein) leads to charcot-marie-tooth
polyneuropathy syndrome
-mutations in proteolipid protein (major myelin protein in CNS) leads to PelizaeusMerzbacher disease causing paraplegia nad early death