X-ray crystallography studies at the Stanford Synchrotron Radiation Laboratory
recently shone light on a human enzyme that helps synthesize heme, the
iron-containing pigment that helps carry oxygen to all parts of our bodies.
There are many enzymes along the chemical pathway that produces heme. Defects
in any one of the enzymes cause different types of porphyria, a set of symptoms
that includes acute pain, neurological problems, and even the madness suffered
by King George III.
Researchers from the University of Texas Medical School gained new insight into
one of these enzymes, called coproporphyrinogen oxidase, or CPO. CPO executes
one of the later steps in making heme, and when defective, is responsible for a
hereditary type of porphyria that causes acute attacks of abdominal pain,
hypertension, tachycardia and neurological dysfunction. Like a broken tool
near the end of an assembly line, defective CPO cannot remove a chemical group
that readies the proto-heme for its next step on the assembly line. An excess
of substrate for the enzyme builds up in the body, causing at times
life-threatening conditions. As well, not enough heme is produced. If
diagnosed early, this type of porphyria can be treated with a high carbohydrate
diet and the addition of heme through an I.V.
The x-ray crystal structure of human CPO revealed the enzyme's novel topology,
and an unexpected molecule (citrate) bound to the enzyme's active site, where
chemical reactions occur. The information has allowed the researchers to
propose two models for how the CPO enzyme catalyzes the reactions leading to
heme. It also shows how mutations in the enzyme cause it to fail at its vital
job.
Heme belongs to a group of pigments called porphyrins that are essential to all
life. Other members include chlorophyll, used by plants for photosynthesis,
and cyanocobalamin, also known as vitamin B12.
To learn more about this research see the full scientific highlight at:
http://www-ssrl.slac.stanford.edu/
research/highlights_archive/cpo.html
Lee DS, Flachsova E, Bodnarova M, Demeler B, Martasek P, Raman CS. Structural
basis of hereditary coproporphyria. Proc Natl Acad Sci USA. 2005 Oct
4;102(40):14232-7.
