Disturbances of Aminoacid Metabolism


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      Dietary aminoacids (derived from the digestion of proteins) are deaminated and their amino group is disposed of in the urea cycle. Each aminoacid has its own catabolic pathway that allows the organism to derive energy from it. Aminoacids that can be converted to glycolytic intermediates and metabolyzed using the pathways of sugars are called glycogenic (in red in the figure below); aminoacids which can be converted to lipid-like products or acetil-CoA are called lipogenic (in blue in the figure below). Some aminoacids are split in two metabolytes, one lipogenic, the other glycogenic. The metabolism of Met, Ile and Val yields propionyl-CoA, which is common with the metabolism of uneven carbon fatty acids, but is a glycogenic metabolyte given that it is converted to succinyl-CoA and, via the Krebs cycle, to oxalacetic acid. When metabolytes of the Krebs cycle are produced, these are converted to oxalacetic acid, and this, in turn, is converted to piruvic acid for energy production. Several genetically determined defects of the metabolism of aminoacids are known some of them causing severe symptoms.

The fuel of the Krebs cycle is acetyl-CoA; thus reaching the intermediates of the Krebs cycle does not really ends the metabolic journey of aminoacids: it is necessary to convert oxaloacetate to acetil-CoA. This is accomplished by the enzyme P-enol piruvate carboxykinase which converts oxaloacetate to P-enolpiruvate, a glycolysis intermediate, from which piruvate can be obtained and, via piruvate dehydrogenase, acetyl-CoA.

      Some of the considerations given for the defects of the urea cycle also apply to defects of aminoacid metabolism. We add that: (i) in several cases, defects of aminoacid metabolism lead to overproduction of soluble metabolic intermediates that the kidney may eliminate; this reduces the severity of the disease. (ii) Careful dietary prescriptions may alleviate the symptoms by reducing the load of the aminoacid whose metabolism is impaired.
      The symptoms of hereditary defects of aminoacid metabolism are congenital or appear very early after birth, but contrary to the defects of the urea cycle, they are very variable; thus these are pediatric diagnoses. Mental retardation, possibly accompanied by seizures, is common to many of these defects; metabolic acidosis with increased anion gap (HAGMA), and/or Fanconi's syndrome (impaired reabsorption of solutes in the renal proximal tubuli, with glycosuria in the absence of hyperglycemia, phosphaturia, and loss of aminoacids and bicarbonate) occur in some of them. Some of these defects are mild or subclinical (e.g. alkaptonuria), others may cause extremely peculiar symptoms (e.g. albinism; urine smell like maple syrup in maple syrup urine disease). Diagnosis requires identification of the biochemical anomaly, and is confirmed by gene sequencing; aminoacid or their abnormal metabolytes are present in the blood and, at higher concentration, in the urine, which in many of these diseases is the biological sample of choice.
      9 aminoacids are essential (i.e. they need to be introduced with the diet, because humans do not have the enzymes required for their biosynthesis: phenylalanine (Phe), valine (Val), threonine (Thr), tryptophan (Trp), methionine (Met), leucine (Leu), isoleucine (Ile), lysine (Lys), and histidine (His). Genetic diseases in these cases are possible only for their catabolic pathways. Deficiency syndromes are described if their availability in the diet is insufficient.
      6 aminoacids are conditionally essential: arginine (Arg), cysteine (Cys), glycine (Gly), glutamine (Gln), proline (Pro), and tyrosine (Tyr). For these we have biosynthetic pathways but their biosynthesis may not be sufficient for our requirements or may depend on poorly available precursors (e.g. Tyr is produced from Phe; Cys from Met), or their decradation may be too effective (Arg). For these we have both biosynthetic and degradation pathways, and both can be affected by genetic diseases.
      5 aminoacids are non essential: alanine (Ala), aspartic acid (Asp), asparagine (Asn), glutamic acid (Glu), serine (Ser). These are produced from widely available intermediates of glycolysis or the Krebs cycle. Given their proximity to major metabolic pathways these are uusually not affected by genetic diseases.

Audio: Hereditary defects of aminoacid metabolism

Hereditary defects of aminoacid metabolism
Disease name Enzymatic defect Organs affected and symptoms Laboratory findings
Tyrosine and Phenylalanine
Phenylketonuria Hereditary deficiency of Phenylalanine hydroxylase (autosomal, recessive)Mental retardation (can be prevented by a diet poor in phenylalanine and tyrosine) Phenylpiruvic acid and other phenylketones in the urine; excess Phe in the blood
Tyrosinosis (Medes) Deficiency of Tyrosine alpha-ketoglutarate transaminase Mental retardation of variable severity excess Tyr in the blood
Tyrosinemia Deficiency of Fumarylacetoacetate hydrolase Fanconi's syndrome; liver failure excess Tyr in the blood
Alkaptonuria deficiency of Homogentisic oxidase benign (urine exposed to oxygen turns black) homogentisic acid in the urine
Albinism deficiency of Tyrosinase Absent melanine; hypopigmentation of the skin
Histidinemia (classic) Histidine ammonia lyase (liver and skin) Mental retardation of variable severity excess His in the blood
Histidinemia (variant) Histidine ammonia lyase (liver) Neurological damage; convulsive cryses; possible coma and death excess His in the blood
Branched chain aminoacidis (Valine, Leucine, and Isoleucine)
Maple syrup urine Disease Branched chain ketoacid decarboxylase Faticability; muscular cramps on exercise metabolic ketoacidosis: branched chain ketoacids in the serum
Valinemia deficiency of Valine aminotransferase Mental retardation of variable severity excess Val in the blood
Methylmalonic acidemia deficiency of Methylmalonyl-CoA mutase Mental retardation, acidosis and coma metabolic acidosis due to methylmalonic acid in the blood (and in the urine)
Sulfur containing aminoacids: Cysteine and Methionine
Homocystinemia deficiency of Cystathionine synthetase Skeletal abnormalities, mental retardation, thrombosis presence of homocysteine in the blood
Cystathioninemia deficiency of Cystathionase (Cystathionine Lyase) Skeletal abnormalities, mental retardation, thrombosis Cystathionine in the blood
Glycine and beta-alanine
Glycinemia deficiency of enzymes of the glycine degradation pathway Convulsive disease, mental retardation excess Gly in the blood
beta-alaninemia deficiency of beta-alanine aminotransferase Convulsive disease, possible coma and death presence of beta-Ala in the blood
Proline and hydroxyproline
Prolinemia, tipe I deficiency of Proline oxidase Nephritis (benign) excess Pro in the blood
Prolinemia, tipe II deficiency of Pyrroline 5-carboxylate dehydrogenase Mental retardation, convulsive disease excess Pro in the blood
Hydroxyprolinemia deficiency of Hydroxyproline oxidase Mental retardation presence of hydroxy-Pro in the blood
Lysinemia deficiency of Lysine ketoglutarate reductase Mental retardation; muscle weakness excess Lys in the blood
Saccharopinuria deficiency of saccharopine dehydrogenase (aminoadipic semialdheyde glutamate reductase; saccharopine pathway) Mental retardation Saccharopine in the blood and urine
Lysine intolerance deficiency of Lysine NAD oxidoreductase (pipecolate pathway) Vomiting, coma
Non proteic aminoacids
Ornithinemia Deficiency of Ornithine transaminase Athrophy of the choroid and retina Ornithine in the blood
Genetically determined disturbances of aminoacid transport
Hartnup diseasemembrane transporter for monoaminomonocarboxylic aminoacidsNeurological symptoms, vitamin B6 deficiencyTrp, Phe, Met, and other aminoacids in the urine
Cystinosis or cystinuria   Nephrolythiasis, renal insufficiency, Fanconi's syndrome presence of cystine (disulfide bond Cys dimer) in the urine

Audio: Metabolic acidosis and defects of aminoacid metabolism

      Laboratory diagnosis of hereditary defects of aminoacid metabolism is very important because dietary restrictions may mitigate or avoid mental retardation and other symptoms. As usual the main problem is suspecting the disease and asking the laboratory for the appropriate test. As a general rule, an aminoacid or its metabolyte will be present in the serum and urine; and since the differential diagnosis cannot be effected on clinical grounds, the different diseases often resembling each other, it is reasonable to measure all the possible metabolytes listed in the table. A possible association that may call your attention is mental retardation and metabolic acidosis. Once the aminoacid or metabolyte has been identified, and a diagnosis is suspected, confirmation may be obtained by means of gene sequencing.


      Some aminoacids have so simple metabolic pathways that genetic diseases are virtually unknown; e.g. alanine is transaminated to piruvate in a single reaction step. Other aminoacids may have complex metabolic pathways requiring several enzymes, and prone to disease.

GLYCINE. In spite of its simple formula and its different possible catabolic pathways, diseases due to genetic defects of Gly catabolism are described. It is interesting to point out that one of Gly catabolic pathways produces oxalic acid, which is excreted by the kidney and may precipitate in the form of calcium oxalate forming urinary stones. Thus imbalances in Gly metabolism (inherited or acquired), may be associated to urolythiasis.

Ala, Ser, Glu, Gln, Asp, Asn are deaminated by single enzymes to produce piruvate, β-ketoglutarate or oxaloacetate. These are metabolytes of the Krebs cycle or glycolysis. Since these pathways are always confirmed diseases of the metabolism of the above aminoacids essentially do not occur.

PHENYLALANINE AND TYROSINE. Phenylalanine(Phe) and tyrosine (Tyr) can be interconverted in a reaction catalyzed by phenylalanine hydroxylase, thus they share common metabolic pathways, and the relative disturbances. Phe and Tyr are essential aminoacids, for which humans do not possess biosynthetic pathways. Their catabolism is specially complex because besides their degradation pathway, leading to fumarate and acetoacetate, they are the precursors of catecholamine hormones (dopamine, adrenaline and noradrenaline), and of melanins the skin pigments responsible for the color of our skin and hair.
      The catabolism of Phe and Tyr leads to fumarate and acetoacetate; important intermediates are p-hydroxyphenyl piruvate and homogentisate. The metabolic pathway is depicted below (in black the enzymes catalyzing each reaction step; in red the genetic disease due to their deficiency):

      The biosynthesis of melanins, the pigments responsible fo the color of our skin, iris and hair starts from the oxidation of Tyr by the enzyme tyrosinase. A genetic defect of tyrosinase causes albinism, the lack of skin pigments.

HISTIDINE. His is converted to glutamic acid in a short metabolic pathway whose first step of this pathway is catalyzed by the enzyme His ammonia lyase and produces one molecule of ammonia. At keast two different genetic defects of this enzyme are described and cause variants of the severe inherited disease histidinemia.

PROLINE and ARGININE are converted to glutamic acid. One genetic disease is described for the catabolism of Pro, prolinemia, due to the defect of proline oxidase, and two diseases are described for the catabolism of Arg, argininemia and ornithinemia. Arginase, the enzyme whose defect causes argininemia belongs to the urea cycle and was described together with other genetic defects of that cycle.

BRANCHED CHAIN AMINOACIDS and PROPIONYL-CoA. Branched chain aminoacids (Val, Leu, Ile) have a partly common pathway whose most important inherited defect are valinemia, due to the absence of the relative transaminase, and maple syrup urine disease, due to the absence of branched chain ketoacid decarboxylase:

Moreover, the catabolism of branched chain amnoacids is among the main producers of propionyl-CoA, a metabolyte common also to the catabolism of uneven C fatty acids and other pathways. A defect of the enxyme methylmalonyl-CoA mutase or of the metabolism of vitamin B12 (required as a cofactor of methylmalonyl-CoA mutase), cause accumulation of methylmalonyl-CoA which spontaneously looses CoA-SH and is converted to methylmalonic acid. Methylmalonic acid is excreted in the urine, but its accumulation in the blood causes a metabolic acidosis (methylmalonic acidemia or aciduria). This metabolyte is easily identified in the serum or in the urine by the clinical laboratory.

LYSINE. The catabolism of the essential aminoacid lysine is extremely complex. Two main pathways are described, both of which can be affected by inheritable diseases: the saccharopine pathway, occurring partly in the cytoplasm and partly in the mitochondria, and the pipecolate pathway, occurring partly in the cytoplasm and partly in the peroxisomes. The two pathways converge at the common intermediate α-aminoadipic semialdehyde. Many organs carry out Lys catabolism, but the principal one is the liver, which mainly uses the saccharopine pathway. The brain is atypical in that it mainly uses the pipecolate pathway.

METHIONINE. Met is an essential aminoacid which plays two major functions: is a constituent of proteins, and a constituent of the coenzyme S-adenosyl-methionine (SAM), a methyl group donor. The catabolism of Metis complex because: (i) it requires conersion to SAM; (ii) it is partially reversible (i.e. one of its products homocysteine can be converted back to Met); (iii) it is also the biosynthetic pathway of Cys.
      There are two important inherited disease of Met catabolism, which cause an increase in the plasma concentration of homocysteine and cystathionine. Homocysteinemia is due to a defect of the enzyme cystathionine synthase. Two variants of the defect are known, one of which can be treated with administration of high doses of vitamin B6 (pyridoxine), the cofactor of cystathionine synthase. Homocysteinemia may cause mental retardation and very early atherosclerosis. The laboratory diagnosis relies upon the finding of high concentrations of homocysteine in the blood and in the urine. Cystathioninemia is due to the defect of cystathionine lyase and causes an increase of cystathionine in the plasma and in the urine.


      Hartnup disease strictly speaking is not a defect of aminoacid metabolism, but a defect of their absorption in the gut and in the renal tubuli. It is inherited as an autosomal recessive trait affecting a membrane transporter for monoaminomonocarboxylic aminoacids. Tryptophan, phenilalanine, methionine and other aminoacids appear in the urine. The defect of tryptophan absorption in the gut is specially relevant, because this aminoacid, besides being essential, is the precursor of vitamin B6 (niacine, the precursor of NADH and NADPH). As a consequence, in Hartnup disease one may observe the cutaneous and neurological symptoms of vitamin B6 deficiency (pellagra). Diagnosis is based on the identification of multiple aminoacids in the urine, together with triptophan metabolytes. The prognosis is good provided that an adequate dietary regimen is instituted.

      Cystinuria is a defect of aminoacid transport, conceptually similar to Hartnup disease. The aminoacids that appear in the urine are lysine, arginine, ornithine and cystine (the dimer of cysteine). Cysteine, being poorly soluble precipitates yielding yellow calculi, that strongly suggest the diagnosis; confirmation comes from the demonstration of above-mentioned aminoacids in the urine. Cystinuria is inherited as an autosomal recessive trait and is relatively benign, nephrolythiasis being the most important symptom; however on the long run renal insufficiency may develop.

Audio: Hereditary defects of aminoacid transport


      The diagnosis of inherited defects of the metabolism of aminoacids is difficult. Each singe disease is rare, but since these diseases are many, their cumulative incidence is significant, probably in the order of 2-4 per one thousand births. All these diseases manifest themselves early in extrauterine life, thus diagnosis is usually called for in the first months of life. The correct diagnosis is important because the baby is usually normal at birth, and specific dietary restriction may in some cases prevent brain damage.
      Babies presenting somnolescence, stunted growth, seizures, etc. should be investigated for inherited metabolic defects. Familial anamnesis may offer some clue, but is often negative, these diseases being inherited as recessive traits. A good starting point is the determination of the concentration of the 20 aminoacids in the serum and the urine by means of high performance liquid chromatography and mass spectrometry. This exam may reveal the abnormal aminoacid, or may reveal the presence of an abnormal compound, not corresponding to any aminoacid, but possibly indicative of one of their metabolytes. The screening of the most common of these diseases, phenylketonuria is routinely carried out at birth by measuring the concentration of phenylpiruvic acid in the urine. A hemogas analysis may reveal a metabolic acidosis with increased anion gap, indicative of the presence of an acidic metabolyte in the serum.
      Once the presence of an abnormal metabolyte in the urine or in the serum has been detected, it can usually be identified by chemical or enzymatic methods. The diagnostic suspicion should be confirmed by gene sequencing. It is advisable to submit to genetic sequencing also the baby's parents, for genetic counseling.

Further readings
BK Burton Inborn Errors of Metabolism in Infancy: A Guide to Diagnosis. Pediatrics 1998; 102: (6) e69.
J Häberle, A Chakrapani, N Ah Mew, and N Longo Hyperammonaemia in classic organic acidaemias: a review of the literature and two case histories
SC Sreenath Nagamani, A Erez, and B Lee Argininosuccinate Lyase Deficiency.
Andre' A. and Jamie J.F. Lysine metabolism in mammalian brain: an update on the importance of recent discoveries . Amino Acids 2013, 45: 1249-72.

Questions and exercises:
1) Hyperammoniemia suggests:
An hereditary defect in aminoacid metabolism
An hereditary defect of the urea cycle
An hereditary defect of aminoacid transport

2) Phenylketonuria is among the most common hereditary defects of metabolism; the aminoacid whose metabolism is impaired is/are:
Phenylalanine and tyrosine

3) Inherited defects of aminoacid metabolism may cause metabolic acidosis. In these cases the anion gap is

4) All genetic defects of the urea cycle are inherited as autosomal recessive traits, except for the following one, which is sex-linked:
deficiency of ornythine transcarbamoylase
arginino succinic acidemia

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Thank you Professor (lecture on bilirubin and jaundice).

The fourth recorded part, the one on hyper and hypoglycemias is not working.
Bellelli: I checked and in my computer it seems to work. Can you better specify
the problem you observe?

This Presentation (electrolytes and blood pH) feels longer than previous lectures
Bellelli: it is indeed. Some subjects require more information than others. I was
thinking of splitting it in two nest year.

Bellelli in response to a question raised by email: when we compare the blood pH
with the standard pH we do not mean to compare the "normal" blood pH (7.4)
with the standard pH. Rather we compare the actual blood pH of the patient, with
the pH of the same blood sample equilibrated under standard conditions.
Thus, if we say that standard pH is lower than pH we mean that equilibriation with
40 mmHg CO2 has caused absorption of CO2 and has lowered the pH with respect
to its value before equilibration.

(Lipoproteins) Is the production of leptin an indirect cause of type 2 diabetes since
it works as a stimulus to have more adipose tissue that produces hormones?
Bellelli: in a sense yes, sustained increase of leptin causes the hypothalamus to adapt
and to stop responding. Obesity ensues and this in turn may cause an increase in the
production of resistin and other insulin-suppressing protein hormones produced by the
adipose tissue. However, this is quite an indirect link, and most probably other factors
contribute as well.

(Urea cycle) what is the meaning of "dissimilatory pathway"?
Bellelli: a dissimilatory pathway is a catabolic pathway whose function is not to produce
energy, but to produce some terminal metabolyte that must be excreted. Dissimilatory
pathways are necessary for those metabolytes that cannot be excreted as such by the
kidney or the liver because they are toxic or poorly soluble. Examples of metabolytes
that require transformation before being eliminated are heme-bilirubin, ammonia,
sulfur and nitrogen oxides, etc.

Talking about IDDM linked neuropathy can be the C peptide absence considered a cause of it??
Bellelli: The C peptide released during the maturation of insulin, besides being an indicator
of the severity of diabetes, plays some incompletely understood physiological roles. For
example it has been hypothesized that it may play a role in the reparation of the
atherosclerotic damage of the small arteries. Thus said, I am not aware that it plays a direct
role in preventing diabetic polyneuropathy. Diabetic neuropathy has at least two causes: the
microvascular damage of the arteries of the nerve (the vasa nervorum), and a direct
effect of hyperglycemia and decreased and irregular insulin supply on the nerve metabolism.
Diabetic neuropathy is observed in both IDDM and NIDDM, and requires several years to
develop. Since the levels of the C peptide differ in IDDM and NIDDM, this would suggest
that the role of the C peptide in diabetic neuropathy is not a major one. If you do have
better information please share it on this site!

In acute intermitted porphyria and congenital erythropoietic porphyria why do the end product
of the affected enzymes accumulate instead of their substrate??
Bellelli: First of all, congratulations! This is an excellent question.
Remember that a condition is which the heme is not produced is lethal in the foetus; thus
the affected enzyme(s) must maintain some functionality for the patient
to be born and to come to medical attention. All known genetic defects of heme
biosynthesis derange but do not block this metabolic pathway.
Congenital Erythropoietc Porphyria (CEP) is a genetic defect of uroporphyrinogen
III cosynthase. This protein associates to uroporphyrinogen synthase (which is present
and functional in CEP) and guarantees that the appropriate uroporphyrinogen isomer is produced
(i.e. uroporphyrinogen III). In the absence of a functional uroporphyrinogen III
cosynthase other possible isomers of uroporphyrinogen are produced together with
uroporpyrinogen III, mostly uroporphyrinogen I. The isomers of uroporphyrinogen
that are produced differ because of the positions of propionate and acetate side chains,
and this in turn is due to the pseudo symmetric structure of porphobilinogen. Only
isomer III can be further used to produce protoporphyrin IX. Thus in the
case of CEP we observe accumulation of abnormal uroporphyrinogen derivatives, which, as
you correctly observed are the products of the enzymatic synthesis operated by
uroporphyrinogen synthase.
The case of Acute Intermittent Porphyria (AIP) is similar, although there may be variants
of this disease. What happens is that either the affected enzyme is a variant that does not
properly associate with uroporphyrinogen III cosynthase or presents active site mutations
that impair the proper alignement of the phoprphobilinogen substrates. In either case
abnormal isomers of uroporphyrinogen are produced, as in CEP.
Also remark that in both AIP and CEP we observe accumulation of the porphobilinogen
precursor: this is because the overall efficiency of the biosynthesis of uroporphyrinogens is
reduced. Thus: (i) less uroporphyrinogen is produced, and (ii) only a fraction of the
uroporphyrinogen that is produced is the correct isomer (uroporphyrinogen III).

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