368

DATE-RAPE DRUGS WITH EMPHASIS ON GHB

TABLE 11.2 Some Monocarboxyla te Transporters for GHB

inCytoplasmic Membranes
a

Abbrevia tion Syn onym NC BI Acces s i o n MCT1

b

SLC16A1 NP_0030 4 2 MCT2

b

S L C 1 6 A 7 O 6 0 6 6 9 MCT4
b

SLC16A4 NP_0046 8 7 SMCT1

c

SLC5A8
d

NP_666018SMC T2
c

S L C 5 A 1 2 Q 1 E H B 4
a

All of these transporters have low substrate afnity and selectivity.

b

H
+

-dependent monocarboxylate transporters 1, 2, and 4.

c

Sodiumcoupled monocarb oxylate transporter s 1 and 2.

Also known as the sodium iodide related cotransporter.

identication n umbers for thre edimensional at

omicresolution struc tures in theProt ein Data Bank (PDB) when th ey are known ( http://www.nc bi.nlm.nih.gov/

;http://www.rcs b.org/pdb/hom e/home.do). Inspection of Tables 11.2 and 11.3 conrms that impressive

progress in knowledge of the molecular and cellular biologyof GH Brelated pathwa ys has been m

ade, but much more remains t o be done.The structures of known and probable chemical intermediates

in the pathways areshown in Figure 11.2. 11.5 BIOSYN THESIS OF E NDOGENOU S GHB11.5.1 First Step fo

r GHB Biosynthesi s in the Known Path way A welldocumented de novo pathway

for the biosynthesis of GHB in brain originates primaril y with glutama te. The pathwa y is shown in F

igure 11.2. Glu ta-mate decarboxylases 1 and 2 yield GABA in mitochondrial matrix. The enzymesare

isozymes of each other, and the relative frequency of occurrence of cDNAclones reveals that the mRNAs are

highly to well expressed in all human tissues(http://w ww.ncbi.nlm.ni h.gov/IEB/Rese arch/Acembly/) . Minor

amounts of GABAalso aris e by deaminati on of the polya mines spermin e, ornithine, an d putresine(Till

akaratne et al., 1995). 11.5.2 Secon d Step for GHB Biosynt hesis in the Known Path way

GABA transaminase reacts GABA with 2oxoglutarate to produce succinic semialdehyde (SSA)

plus glutamate in mitochondrial matrix (Figure 11.2). The reactiontransfer s the pro-( S

)-hydrogen from GABA (Santaniello et al., 1978). Only onegene exists for human GABA transaminase.

The mature polypeptide is 472 aminoacids lon g, M

r

53.3 kDa, and a soluble hom odimer (Schou sboe et al., 19 80;Kugler, 1993; Rao and Murthy, 1993). The relative

frequency of cDNA cloneshas revealed that the mRNA is expressed at high to moderate levels

in essentiallyall h uman tissues (http://www.nc bi.nlm.nih.gov/I EB/Research/A cembly/).

15

GABA