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8 Metabolism S. Silbernagl

Overview Amino Acids
Metabolic abnormalities are frequently caused Amino acids (AA) are both building blocks and
by faulty endocrine regulation (e.g., diabetes breakdown products of proteins. They are the
mellitus; → 286ff.), or genetic defects of en- precursors of hormones and transmitters, pu-
zymes (enzymopathies) or of transport pro- rines, amines, heme, etc., and they serve as en-
teins, the latter, for example, in cystic fibrosis ergy sources. Ammonia, produced during cata-
(→ p.162) and cystinosis (see below). The en- bolism, is incorporated into urea and excreted
docytosis and exocytosis of lipoproteins can in this form. Too many or too few amino acids,
also be affected by defects of apolipoproteins a carrier defect (→ e.g., p. 96ff.), or abnormal
or membrane receptors (→ p. 246ff.). formation of urea (→ p.174) thus usually lead
If there is an enzyme defect (→ A, enzyme to marked disorders. A lack of essential amino
X), the substrate (A) to be metabolized accu- acids may be due to inadequate intake (unbal-
mulates, so that the concentration of A in the anced diet).
cell organelle, in the cell, and/or in the body In phenylketonuria (PKU) the conversion of
rises. This can result in phenylalanine (Phe) to tyrosine (Tyr) is
– substrate A being “stored” and thus becom- blocked (→ B1). If as a result the Phe concen-
ing a problem, if only in terms of space tration in plasma rises above ca. 1 mmol/L,
(storage diseases, e.g., glycogen storage dis- Phe is broken down via secondary pathways,
ease, lipidoses; → p. 244); especially phenylpyruvate that appears in
– toxic effects at high concentrations, or pre- urine (= PKU). In addition, Phe blocks the
cipitation of the substrate because of its transport of certain amino acids, so that these
low solubility, in this way causing damage neither leave parenchymal cells (sequestra-
(e.g., cystine in cystinuria or uric acid/urate tion) nor are able to enter brain cells (→ B). Se-
in gout; → p.120 and 250); vere developmental defects in the brain are the
– conversion of the substrate, via another result. A lack of melanin (→ B), formed from
metabolic pathway (enzyme Z), to a meta- tyrosine, also disturbs pigmentation (light
bolite that is harmful at the increased con- sensitivity). Early diagnosis and a low-Phe
centration (metabolite E); diet can prevent these developmental disor-
– inhibition of the metabolic conversion of ders. Rare forms of PKU are due to a defect of
another enzyme (enzyme Y) or of a carrier dihydropteridine reductase (→ B2).
that is essential for the transport of other Further metabolic disorders of amino acids
substances, too (substrate C). include (the corresponding enzyme defect is
In addition, the primary enzyme defect leads given in brackets): hyperglycinemia (propio-
to a deficiency of the substance formed by nyl-CoA-carboxylase), hyperoxaluria (type I:
this metabolic pathway (→ A, metabolite B). alanine-glyoxylate aminotransferase; type II:
In glycogen storage disease, for example, it D-glycerate dehydrogenase), maple syrup dis-
causes glucose or ATP deficiency (→ p. 244). A ease (multi-enzyme complex in the break-
lack of metabolite B may additionally increase down of branched-chain AA), homocystinuria
the metabolic rate of other enzyme reactions (type I: cystathionine–β-synthase; type II:
(→ A, enzyme Y). methionine resynthesis from homocysteine;
Metabolic disorders play a part in the pro- → p. 34, A2), cystinosis (carrier defect ⇒ lyso-
cesses dealt with in almost every chapter in somal cystine accumulation), alkaptonuria
this book. This chapter describes further ex- (homogentisic acid dioxygenase), oculocuta-
amples of metabolic abnormalities, their se- neous albinism (phenoloxidase = tyrosinase),
lection made mainly according to the serious- and hyperprolinemia (type I: proline dehydro-
ness, treatability (on early diagnosis), and genase; type II: follow-on enzyme), type I
prevalence of the abnormalities. being a partial form of Alport’s syndrome.
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